Pharmacogene expression during progression of metabolic dysfunction-associated steatotic liver disease: Studies on mRNA and protein levels and their relevance to drug treatment.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is common worldwide. Genes and proteins contributing to drug disposition may show altered expression as MASLD progresses. To assess this further, we undertook transcriptomic and proteomic analysis of 137 pharmacogenes in liver biopsies from a large MASLD cohort. We performed sequencing on RNA from 216 liver biopsies (206 MASLD and 10 controls). Untargeted mass spectrometry proteomics was performed on a 103 biopsy subgroup. Selected RNA sequencing signals were replicated with an additional 187 biopsies. Comparison of advanced MASLD (fibrosis score 3/4) with milder disease (fibrosis score 0-2) by RNA sequencing showed significant alterations in expression of certain phase I, phase II and ABC transporters. For cytochromes P450, CYP2C19 showed the most significant decreased expression (30 % of that in mild disease) but significant decreased expression of other CYPs (including CYP2C8 and CYP2E1) also occurred. CYP2C19 also showed a significant decrease comparing the inflammatory form of MASLD (MASH) with non-MASH biopsies. Findings for CYP2C19 were confirmed in the replication cohort. Proteomics on the original discovery cohort confirmed decreased levels of several CYPs as MASLD advanced but this decrease was greatest for CYP2C19 where levels fell to 40 % control. This decrease may result in decreased CYP2C19 activity that could be problematic for prescription of drugs activated or metabolized by CYP2C19 as MASLD advances. More limited decreases for other P450s suggest fewer issues with non-CYP2C19 drug substrates. Negative correlations at RNA level between CYP2C19 and several cytokine genes provided initial insights into the mechanism underlying decreased expression.

Financial and economic costs of healthcare associated infections in Africa.

BACKGROUND: Healthcare associated infections (HAI) remain a global health challenge and have elevated rates in Sub-Saharan Africa. HAIs impact patients and their families by causing illness, prolonged hospital stay, potential disability, excess costs and sometimes death. The costs of HAI are increasing due to spreading antimicrobial resistance. A major risk factor for HAIs is lack of water, sanitation, and hygiene (WASH), environmental cleaning and healthcare waste management. In Sub-Saharan Africa these services are lacking in at least 50% of healthcare facilities. AIM: This study estimated the costs associated with HAIs at national level in fourteen countries in Sub-Saharan Africa. METHODS: Economic methodologies were employed to estimate the medical costs, productivity losses and value of premature death from HAIs, drawing on national statistics and published studies to populate the economic model. RESULTS: In 2022, the number of HAIs was estimated at 4.8 million, resulting in 500,000 deaths. Health-related economic losses amounted to US$13 billion per year, equivalent to 1.14% of combined GDP and US$15.7 per capita. Healthcare costs were US$500 per HAI and represented 5.6% of total health expenditure. The costs of providing basic WASH were US$0.91 per capita, which, if they reduced HAIs by 50%, resulted in benefit-cost ratios of 1.6 (financial health care savings only) and 8.6 (including all economic benefits). CONCLUSION: HAIs have a major health and economic burden on African societies, and a significant share can be prevented. It is critical that health policy makers and practitioners dedicate policy space, resources, and training to address HAIs.

Anti-Vascular Endothelial Growth Factor Drugs Compared With Panretinal Photocoagulation for the Treatment of Proliferative Diabetic Retinopathy: A Cost-Effectiveness Analysis.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness of anti-vascular endothelial growth factor drugs (anti-VEGFs) compared with panretinal photocoagulation (PRP) for treating proliferative diabetic retinopathy (PDR) in the United Kingdom. METHODS: A discrete event simulation model was developed, informed by individual participant data meta-analysis. The model captures treatment effects on best corrected visual acuity in both eyes, and the occurrence of diabetic macular edema and vitreous hemorrhage. The model also estimates the value of undertaking further research to resolve decision uncertainty. RESULTS: Anti-VEGFs are unlikely to generate clinically meaningful benefits over PRP. The model predicted anti-VEGFs be more costly and similarly effective as PRP, generating 0.029 fewer quality-adjusted life-years at an additional cost of £3688, with a net health benefit of -0.214 at a £20 000 willingness-to-pay threshold. Scenario analysis results suggest that only under very select conditions may anti-VEGFs offer potential for cost-effective treatment of PDR. The consequences of loss to follow-up were an important driver of model outcomes. CONCLUSIONS: Anti-VEGFs are unlikely to be a cost-effective treatment for early PDR compared with PRP. Anti-VEGFs are generally associated with higher costs and similar health outcomes across various scenarios. Although anti-VEGFs were associated with lower diabetic macular edema rates, the number of cases avoided is insufficient to offset the additional treatment costs. Key uncertainties relate to the long-term comparative effectiveness of anti-VEGFs, particularly considering the real-world rates and consequences of treatment nonadherence. Further research on long-term visual acuity and rates of vision-threatening complications may be beneficial in resolving uncertainties.

Recent advances in non-Huntington's disease choreas.

INTRODUCTION: Chorea is primarily due to an imbalance of basal ganglia output pathways, often due to dysfunction or degeneration of the caudate nucleus and putamen, and can be due to many causes. METHODS: We reviewed the recent literature to identify newly-recognized causes of chorea, including auto-immune, metabolic, and genetic. We also focused upon developments in mechanisms relating to underlying pathophysiology of certain genetic choreas and advances in therapeutics. RESULTS: Novel autoantibodies continue to be identified as causes of chorea. Both COVID-19 infection and vaccination are reported to result rarely in chorea, although in some cases causality is not clearly established. Advances in genetic testing continue to find more causes of chorea, and to expand the phenotype of known genetic disorders. Deep brain stimulation can be successful in certain circumstances. CONCLUSION: Our understanding of mechanisms underlying this movement disorder continues to advance, however much remains to be elucidated.

Neuroacanthocytosis Syndromes: The Clinical Perspective.

The two very rare neurodegenerative diseases historically known as the "neuroacanthocytosis syndromes" are due to mutations of either VPS13A or XK. These are phenotypically similar disorders that affect primarily the basal ganglia and hence result in involuntary abnormal movements as well as neuropsychiatric and cognitive alterations. There are other shared features such as abnormalities of red cell membranes which result in acanthocytes, whose relationship to neurodegeneration is not yet known. Recent insights into the functions of these two proteins suggest dysfunction of lipid processing and trafficking at the subcellular level and may provide a mechanism for neuronal dysfunction and death, and potentially a target for therapeutic interventions.

Genetic risk variants in New Yorkers of Puerto Rican and Dominican Republic heritage with Parkinson's disease.

There is a paucity of genetic characterization in people with Parkinson's disease (PD) of Latino and Afro-Caribbean descent. Screening LRRK2 and GBA variants in 32 New Yorkers of Puerto Rican ethnicity with PD and in 119 non-Hispanic-non-Jewish European PD cases revealed that Puerto Rican participants were more likely to harbor the LRRK2-p.G2019S variant (15.6% vs. 4.2%, respectively). Additionally, whole exome sequencing of twelve Puerto Rican and Dominican PD participants was performed as an exploratory study.

Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative tauopathy variably affecting brainstem and cortical structures and characterized by tau inclusions in neurons and glia. The precise mechanism whereby these protein aggregates lead to cell death remains unclear. To investigate the contribution of these different cellular abnormalities to PSP pathogenesis, we performed single-nucleus RNA sequencing and analyzed 45,559 high quality nuclei targeting the subthalamic nucleus and adjacent structures from human post-mortem PSP brains with varying degrees of pathology compared to controls. Cell-type specific differential expression and pathway analysis identified both common and discrete changes in numerous pathways previously implicated in PSP and other neurodegenerative disorders. This included EIF2 signaling, an adaptive pathway activated in response to diverse stressors, which was the top activated pathway in vulnerable cell types. Using immunohistochemistry, we found that activated eIF2α was positively correlated with tau pathology burden in vulnerable brain regions. Multiplex immunofluorescence localized activated eIF2α positivity to hyperphosphorylated tau (p-tau) positive neurons and ALDH1L1-positive astrocytes, supporting the increased transcriptomic EIF2 activation observed in these vulnerable cell types. In conclusion, these data provide insights into cell-type-specific pathological changes in PSP and support the hypothesis that failure of adaptive stress pathways play a mechanistic role in the pathogenesis and progression of PSP.

An Autopsy Series of Seven Cases of VPS13A Disease (Chorea-Acanthocytosis).

BACKGROUND: Vacuolar protein sorting 13 homolog A (VPS13A) disease, historically known as chorea-acanthocytosis, is a rare neurodegenerative disorder caused by biallelic mutations in VPS13A, usually resulting in reduced or absent levels of its protein product, VPS13A. VPS13A localizes to contact sites between subcellular organelles, consistent with its recently identified role in lipid transfer between membranes. Mutations are associated with neuronal loss in the striatum, most prominently in the caudate nucleus, and associated marked astrogliosis. There are no other known disease-specific cellular changes (eg, protein aggregation), but autopsy reports to date have been limited, often lacking genetic or biochemical diagnostic confirmation. OBJECTIVE: The goal of this study was to characterize neuropathological findings in the brains of seven patients with VPS13A disease (chorea-acanthocytosis). METHODS: In this study, we collected brain tissues and clinical data from seven cases of VPS13A for neuropathological analysis. The clinical diagnosis was confirmed by the presence of VPS13A mutations and/or immunoblot showing the loss or reduction of VPS13A protein. Tissues underwent routine, special, and immunohistochemical staining focused on neurodegeneration. Electron microscopy was performed in one case. RESULTS: Gross examination showed severe striatal atrophy. Microscopically, there was neuronal loss and astrogliosis in affected regions. Luxol fast blue staining showed variable lipid accumulation with diverse morphology, which was further characterized by electron microscopy. In some cases, rare degenerating p62- and ubiquitin-positive cells were present in affected regions. Calcifications were present in four cases, being extensive in one. CONCLUSIONS: We present the largest autopsy series of biochemically and genetically confirmed VPS13A disease and identify novel histopathological findings implicating abnormal lipid accumulation. © 2023 International Parkinson and Movement Disorder Society.

Sphingolipid and Phospholipid Levels Are Altered in Human Brain in Chorea-Acanthocytosis.

BACKGROUND: Chorea-acanthocytosis (ChAc) is associated with mutations of VPS13A, which encodes for chorein, a protein implicated in lipid transport at intracellular membrane contact sites. OBJECTIVES: The goal of this study was to establish the lipidomic profile of patients with ChAc. METHODS: We analyzed 593 lipid species in the caudate nucleus (CN), putamen, and dorsolateral prefrontal cortex (DLPFC) from postmortem tissues of four patients with ChAc and six patients without ChAc. RESULTS: We found increased levels of bis(monoacylglycerol)phosphate, sulfatide, lysophosphatidylserine, and phosphatidylcholine ether in the CN and putamen, but not in the DLPFC, of patients with ChAc. Phosphatidylserine and monoacylglycerol were increased in the CN and N-acyl phosphatidylserine in the putamen. N-acyl serine was decreased in the CN and DLPFC, whereas lysophosphatidylinositol was decreased in the DLPFC. CONCLUSIONS: We present the first evidence of altered sphingolipid and phospholipid levels in the brains of patients with ChAc. Our observations are congruent with recent findings in cellular and animal models, and implicate defects of lipid processing in VPS13A disease pathophysiology. © 2023 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Comparison of Bayesian methods for incorporating adult clinical trial data to improve certainty of treatment effect estimates in children.

There are challenges associated with recruiting children to take part in randomised clinical trials and as a result, compared to adults, in many disease areas we are less certain about which treatments are most safe and effective. This can lead to weaker recommendations about which treatments to prescribe in practice. However, it may be possible to 'borrow strength' from adult evidence to improve our understanding of which treatments work best in children, and many different statistical methods are available to conduct these analyses. In this paper we discuss four Bayesian methods for extrapolating adult clinical trial evidence to children. Using an exemplar dataset, we compare the effect of their modelling assumptions on the estimated treatment effect and associated heterogeneity. These modelling assumptions range from adult evidence being completely generalisable to being completely unrelated to the children's evidence. We finally discuss the appropriateness of these modelling assumptions in the context of estimating treatment effect in children.

Diagnostic Uncertainties: Chorea.

Chorea is a hyperkinetic movement disorder with a multitude of potential etiologies, both acquired and inherited. Although the differential diagnosis for new-onset chorea is extensive, there are often clues in the history, exam, and basic testing that can help to narrow the options. Evaluation for treatable or reversible causes should take priority, as rapid diagnosis can lead to more favorable outcomes. While Huntington's disease is most common genetic cause of chorea, multiple phenocopies also exist and should be considered if Huntington gene testing is negative. The decision of what additional genetic testing to pursue should be based on both clinical and epidemiological factors. The following review provides an overview of the many possible etiologies as well as a practical approach for a patient presenting with new-onset chorea.

Health and disability care providers' experiences and perspectives on end-of-life care needs of individuals with long-standing physical disability: A qualitative interview study.

BACKGROUND: Little is known about the specific needs and experiences of individuals with long-standing physical disability at end of life. AIM: To explore health and disability care providers perspectives and experiences in relation to end-of-life care needs of individuals with long-standing physical disability. DESIGN: Qualitative study using reflexive thematic analysis. SETTING/PARTICIPANTS: Semi-structured interviews were conducted with nine health and disability care providers from two Australian states. RESULTS: Five themes were constructed from the data: (1) The significance of place. All participants described how the end-of-life care experience was significantly impacted by the place in which dying occurred. (2) Knowing the person and their needs. Knowledge and familiarity with the individual with long-standing disability were seen as invaluable in terms of providing continued high-quality care. (3) Navigating a new care landscape. For disability support workers, struggling to adapt from providing disability support to end-of-life care was difficult. (4) Complexities of family involvement. Past experiences of families within the healthcare system had resultant impacts on care received by the individual with long-standing disability. (5) Being prepared. Participants felt more was needed in terms of end-of-life planning and discussions around end of life for this cohort. CONCLUSIONS: This research highlights a significant lack of continuity of care and problems at the intersection of the disability and health systems when providing end-of-life care for this cohort. Suggested areas for improvement include team approaches to enable continuity of care and dying in place, and a need for knowledge and skills in this area for all stakeholders.

Transgender and Gender Diverse People's Fear of Seeking and Receiving Care in Later Life: A Multiple Method Analysis.

The purpose of the current research is to understand concerns about receiving care in a sample of transgender, gender nonbinary, and gender diverse (TGD) adults across the lifespan. A total of 829 participants, predominantly from the United States and Canada, aged 18-70, completed the Trans Metlife Survey on Later-Life Preparedness and Perceptions in Transgender-Identified Individuals (TMLS) section on caregiving and are included in this study. We found middle-aged adults, people of Color, and people living with a disability reported the highest level of concern for their ability to function independently because of financial resources, physical concerns, cognitive impairment, or a lack of someone to care for them. Researchers found five overarching thematic categories: (a) No concerns, (b) Anticipated discrimination, (c) Loss of control, (d) Quality of life, and (e) General concerns. Practice implications include recommendations for practitioners to develop care plans with TGD residents and clients to learn the best strategies for affirming their gender identity (e.g., clothing preferences) and to assist TGD residents and clients with the completion of advance directives to allow them to outline their end-of-life care plan, including instructions for gender affirmative care in the event of incapacitation (e.g., dementia, stroke).

Barriers to activity engagement in older adulthood: Results of a community survey.

OBJECTIVES: Losses that occur with age can create barriers to meaningful activity engagement, a crucial aspect of ageing well. Research on this topic is frequently qualitative, with few studies accessing large community samples. This study (a) assessed the frequency specific personal and environmental barriers (such as poor health and limited transport access), identified by older adults in previous research, were endorsed; (b) used latent class analysis (LCA) to identify population subgroups based on combinations of these barriers, and (c) examined associations of subgroups with purpose in life and quality of life. METHODS: Four hundred and thirty-two randomly selected Australian adults aged 65+ years (average age 76.7, 58% female) completed a telephone survey. They were asked whether certain barriers affected engagement and provided data on sense of purpose and quality of life. RESULTS: Physical health/mobility were the most frequently reported barriers, followed by sensory difficulties, financial limitations, and caring responsibilities. The LCA revealed up to three subgroups/classes of participants according to the barriers endorsed. Class 1 had low endorsement of all barriers, including physical health. The majority of Class 2 endorsed physical health barriers and other barriers more frequently than Class 1. Class 3 were comparable to Class 2, but also frequently endorsed community access barriers. Class 1 were younger and reported a greater sense of purpose and higher quality of life. CONCLUSIONS: Physical health/mobility barriers to engagement are those most frequently endorsed by older adults. These barriers may increase vulnerability to, or exacerbate the impact of additional barriers, such as sensory difficulties, access to transport and lack of finances.

A novel SYNJ1 homozygous variant causing developmental and epileptic encephalopathy in an Afro-Caribbean individual.

BACKGROUND: SYNJ1 encodes Synaptojanin-1, a dual-function poly-phosphoinositide phosphatase that is expressed in the brain to regulate neuronal synaptic vesicle dynamics. Biallelic SYNJ1 variants cause a spectrum of clinical manifestations, from early onset parkinsonism to developmental and epileptic encephalopathy. METHODS: Proband-only exome sequencing was used to identify a homozygous SYNJ1 pathogenic variant in an individual with epileptic encephalopathy. Sanger sequencing was used to confirm the variant. RESULTS: We present an Afro-Caribbean female who developed uncontrollable seizures shortly after birth, accompanied by developmental delay and severe generalized dystonia. She had homozygosity for a novel c.242-2A > G variant in SYNJ1 with both parents being heterozygous carriers. An older sister was reported to have had a similar presentation but was not examined. Both siblings died at an approximate age of 16 years. CONCLUSIONS: We report a novel pathogenic variant in SYNJ1 present in homozygosity leading to developmental and epileptic encephalopathy. Currently, there are only 4 reports describing 10 individuals with SYNJ1-related developmental and epileptic encephalopathy. This case expands the clinical knowledge and the allelic heterogeneity associated with SYNJ1 variants.

What Quality-of-Life Dimensions Are Most Important to Older Adults from Culturally and Linguistically Diverse Backgrounds Receiving Aged Care Services? An Exploratory Study.

There is little research on what aspects of quality of life (QoL) are most important to culturally and linguistically diverse (CALD) older adults. This study aimed to identify what QoL dimensions were most important to CALD older adults receiving aged care services, and therefore, how relevant a new six dimensions QoL instrument developed for use in aged care is to this population. A three-stage, mixed-methods study was undertaken. Stage 1: n = 3 focus groups with aged care providers. Stage 2: n = 30 semi-structured interviews with Italian-born older adults in ethno-specific residential aged care. Stage 3: survey of n = 63 older adults from mixed CALD backgrounds receiving community aged care services. Overall, older adults asserted the importance of the six dimensions of the new QoL instrument. The importance of 'identity' and 'purpose and meaning' were identified via the focus groups; however, the community-based CALD older adults identified these aspects of quality of life as more important than older Italians in residential care. Being in ethno-specific residential aged care where needs relating to language, food, and religion were met and they continued to live with others from their community may have meant that the meeting of cultural needs was more taken for granted.

Extent and nature of duplication in PROSPERO using COVID-19-related registrations: a retrospective investigation and survey.

OBJECTIVES: During COVID-19, the International Prospective Register of Systematic Reviews (PROSPERO) experienced a surge in registrations for COVID-19-related systematic reviews, and duplication of research questions became apparent. Duplication can waste funding, time and research effort and make policy making more difficult.This project explored the extent of and reasons for duplication of COVID-19-related systematic review registrations in PROSPERO during the pandemic. DESIGN: Retrospective analysis of COVID-19-related registrations in PROSPERO, and a qualitative survey. SETTING: PROSPERO was searched for registrations related to four COVID-19 research areas: epidemiology, rehabilitation, transmission and treatments. METHODS: Records identified were compared using Population, Intervention/Exposure, Comparator, Outcome, Study Design (PICOS) elements of PROSPERO registration forms. Registrations with similar or identical PICOS were evaluated further as 'duplicates'.Authors of 'duplicate' registrations were invited to complete a survey asking whether they searched PROSPERO prior to registration, identified similar reviews and, if so, why they continued with their review. RESULTS: 1054 COVID-19 reviews were registered between March 2020 and January 2021, of which 138 were submitted when at least one similar protocol was already registered in PROSPERO. Duplication was greatest in reviews of COVID-19 treatments; for example, there were 14 similar reviews evaluating the efficacy of hydroxychloroquine.From 138 authors invited to take part in the survey, we received 41 responses. Most respondents said that they identified similar reviews when they searched PROSPERO prior to registration. Main reasons given for 'duplication' were differences in PICOS or planned analyses (n=13), poor quality of previous registrations (n=2) and the need to update evidence (n=3). CONCLUSIONS: This research highlights that registration of similar and duplicate systematic reviews related to COVID-19 in PROSPERO occurred frequently. Awareness of research waste is required, and initial checking for similar reviews should be embedded within good review practice.

A behavioural activation intervention to increase engagement with life and wellbeing in older adults: Study protocol for a randomised controlled trial.

BACKGROUND: Meaningful activity engagement is a critical element of ageing well. Interventions designed to increase activity engagement tend to be activity-specific and do not always meet the needs of older adults with diverse interests and capacities. Behavioural activation (BA) provides a promising person-centred framework for promoting engagement in valued activities. This study will examine the effectiveness of a behavioural activation-based intervention for promoting engagement with life and wellbeing among older adults. METHOD: Participants will be randomly allocated to one of two conditions (BA intervention, Active Control) and take part in a six-week intervention that consists of one-on-one weekly sessions of up to one hour to be administered either via telephone or online video conferencing with a trained facilitator. This study will recruit 120 + participants aged 65 + who score at or below the median on a test of life engagement. Participants will complete questionnaires of primary and secondary measures both pre-program, one-week and three months post-program. Participants will also complete a daily diary questionnaire during the fourth and fifth weeks of the intervention. The primary outcome measure is the Life Engagement Test, and secondary outcome measures include assessments of subjective wellbeing, psychological wellbeing, mental health, self-reported health, social engagement, loneliness and life satisfaction. DISCUSSION: The outcomes from this study will provide evidence as to whether a BA based approach represents an effective method for promoting engagement with life and wellbeing among older community-dwelling adults. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (Reg no. ACTRN 12621001192875). Trial retrospectively registered 6th September, 2021.