The experience of an adult diabetic foot unit continuing face-to-face consults during the COVID-19 pandemic.

BACKGROUND AND AIMS: The COVID-19 pandemic significantly disrupted lower limb diabetes care. We aimed to map trends in diabetes-related lower limb amputation and hospitalisation rates through the COVID-19 pandemic. METHODS: We performed a retrospective cohort study of all individuals who underwent a lower limb amputation for a diabetes-related foot complication from 2018 to 2021 at the Royal Melbourne Hospital, a quaternary hospital in Australia. Hospitalisation rates with a diabetes-related foot complication were collected for comparison. The start of the COVID-19 epoch was defined as 16 March 2020, when a state of emergency was declared in Melbourne. RESULTS: During the study period, 360 lower limb amputations for diabetes-related foot complications were performed in 247 individuals. The median monthly number of amputations remained stable prior to and during the COVID-19 epoch; there was a median of 8.0 amputations per month (interquartile range (IQR) = 6.5-11) before COVID-19, compared to 6.5 amputations (IQR = 5.0-8.3) during the COVID-19 epoch (P = 0.23). Hospitalisation with a diabetes-related foot complication significantly increased from a median monthly rate of 11 individuals (IQR = 9.0-14) before COVID-19 to 19 individuals (IQR = 14-22) during the COVID-19 epoch (p < 0.001). CONCLUSIONS: Despite increased hospitalisations for diabetes-related foot complications during COVID-19, there was not a corresponding increase in amputation rates. Face-to-face care of diabetes-related foot complications was prioritised at this centre and may have contributed to stable amputation rates during the pandemic.

Forecasting the daily demand for emergency medical ambulances in England and Wales: a benchmark model and external validation.

BACKGROUND: We aimed to select and externally validate a benchmark method for emergency ambulance services to use to forecast the daily number of calls that result in the dispatch of one or more ambulances. METHODS: The study was conducted using standard methods known to the UK's NHS to aid implementation in practice. We selected our benchmark model from a naive benchmark and 14 standard forecasting methods. Mean absolute scaled error and 80 and 95% prediction interval coverage over a 84 day horizon were evaluated using time series cross validation across eight time series from the South West of England. External validation was conducted by time series cross validation across 13 time series from London, Yorkshire and Welsh Ambulance Services. RESULTS: A model combining a simple average of Facebook's prophet and regression with ARIMA errors (1, 1, 3)(1, 0, 1, 7) was selected. Benchmark MASE, 80 and 95% prediction intervals were 0.68 (95% CI 0.67 - 0.69), 0.847 (95% CI 0.843 - 0.851), and 0.965 (95% CI 0.949 - 0.977), respectively. Performance in the validation set was within expected ranges for MASE, 0.73 (95% CI 0.72 - 0.74) 80% coverage (0.833; 95% CI 0.828-0.838), and 95% coverage (0.965; 95% CI 0.963-0.967). CONCLUSIONS: We provide a robust externally validated benchmark for future ambulance demand forecasting studies to improve on. Our benchmark forecasting model is high quality and usable by ambulance services. We provide a simple python framework to aid its implementation in practice. The results of this study were implemented in the South West of England.

Pak2 as a Novel Therapeutic Target for Cardioprotective Endoplasmic Reticulum Stress Response.

RATIONALE: Secreted and membrane-bound proteins, which account for 1/3 of all proteins, play critical roles in heart health and disease. The endoplasmic reticulum (ER) is the site for synthesis, folding, and quality control of these proteins. Loss of ER homeostasis and function underlies the pathogenesis of many forms of heart disease. OBJECTIVE: To investigate mechanisms responsible for regulating cardiac ER function, and to explore therapeutic potentials of strengthening ER function to treat heart disease. METHODS AND RESULTS: Screening a range of signaling molecules led to the discovery that Pak (p21-activated kinase)2 is a stress-responsive kinase localized in close proximity to the ER membrane in cardiomyocytes. We found that Pak2 cardiac deleted mice (Pak2-CKO) under tunicamycin stress or pressure overload manifested a defective ER response, cardiac dysfunction, and profound cell death. Small chemical chaperone tauroursodeoxycholic acid treatment of Pak2-CKO mice substantiated that Pak2 loss-induced cardiac damage is an ER-dependent pathology. Gene array analysis prompted a detailed mechanistic study, which revealed that Pak2 regulation of protective ER function was via the IRE (inositol-requiring enzyme)-1/XBP (X-box-binding protein)-1-dependent pathway. We further discovered that this regulation was conferred by Pak2 inhibition of PP2A (protein phosphatase 2A) activity. Moreover, IRE-1 activator, Quercetin, and adeno-associated virus serotype-9-delivered XBP-1s were able to relieve ER dysfunction in Pak2-CKO hearts. This provides functional evidence, which supports the mechanism underlying Pak2 regulation of IRE-1/XBP-1s signaling. Therapeutically, inducing Pak2 activation by genetic overexpression or adeno-associated virus serotype-9-based gene delivery was capable of strengthening ER function, improving cardiac performance, and diminishing apoptosis, thus protecting the heart from failure. CONCLUSIONS: Our findings uncover a new cardioprotective mechanism, which promotes a protective ER stress response via the modulation of Pak2. This novel therapeutic strategy may present as a promising option for treating cardiac disease and heart failure.

A retrospective analysis of hand tapping as a longitudinal marker of disease progression in Huntington's disease.

BACKGROUND: Current clinical assessments of motor function in Huntington's Disease (HD) rely on subjective ratings such as the Unified Huntington's Disease Rating scale (UHDRS). The ability to track disease progression using simple, objective, inexpensive, and robust measures would be beneficial. METHODS: One objective measure of motor performance is hand-tapping. Over the last 14 years we have routinely collected, using a simple device, the number of taps made by the right and left hand over 30 seconds in HD patients attending our NHS clinics. RESULTS: Here we report on a longitudinal cohort of 237 patients, which includes patients at all stages of the disease on a wide range of drug therapies. Hand tapping in these patients declines linearly at a rate of 5.1 taps per year (p < 0.0001; 95% CI = 3.8 to 6.3 taps), and for each additional year of age patients could perform 0.9 fewer taps (main effect of age: p = 0.0007; 95% CI = 0.4 to 1.4). Individual trajectories can vary widely around this average rate of decline, and much of this variation could be attributed to CAG repeat length. Genotype information was available for a subset of 151 patients, and for each additional repeat, patients could perform 5.6 fewer taps (p < 0.0001; 95% CI = 3.3 to 8.0 taps), and progressed at a faster rate of 0.45 fewer taps per year (CAG by time interaction: p = 0.008; 95% CI = 0.12 to 0.78 taps). In addition, for each unit decrease in Total Functional Capacity (TFC) within individuals, the number of taps decreased by 6.3 (95% CI = 5.4 to 7.1, p < 0.0001). CONCLUSIONS: Hand tapping is a simple, robust, and reliable marker of disease progression. As such, this simple motor task could be a useful tool by which to assess disease progression as well therapies designed to slow it down.

Impacts of gait freeze on quality of life in Parkinson's disease, from the perspectives of patients and their carers.

BACKGROUND: The World Health Organisation (WHO) reports that morbidity and mortality due to Parkinson's disease (PD) are increasing faster than for other neurodegenerative conditions. People with Parkinson's (PwP) present with a variety of motor symptoms, such as tremor, bradykinesia, and rigidity. Freezing of gait (FoG) is a significant motor symptom that manifests as temporary episodes of inability to move one's feet, despite the intention to walk. AIMS: This study examined the impact of FoG on quality of life (QoL) within an Irish cohort of PwP, from the perspectives of both PwP and their carers, using validated questionnaires that had been adapted for online use. METHODS: PwP and their carers were recruited by outreach to the Irish Parkinson's Community. Anonymous online questionnaires were distributed, which combined a demographic survey with several clinically validated surveys, including Freezing of Gait Questionnaire (FoG-Q), Parkinson's Disease Questionnaire 8 (PDQ-8), and Parkinson's Disease Carer Questionnaire (PDQ-C). RESULTS: There was a strong correlation (p < 0.001) between severity of FoG and lower QoL among PwP. Significant correlation was also found between FoG severity and several motor symptoms, such as postural instability and difficulty with balance, and non-motor symptoms, such as cognitive changes and pain/discomfort. FoG severity correlated with disease progression. Significant correlation was also found between FoG and symptoms, as assessed from the perspective of the patients' carers. CONCLUSIONS: This study shows that FoG is a significant detriment to the QoL of PwP, from the perspectives of patients and carers. This method of assessing FoG and QoL using online questionnaires has potential to enhance the reach and flexibility of this type of research. These findings will inform future studies on larger cohorts and highlight unmet clinical needs in PwP.

Atypical fractures at non-classical sites associated with anti-resorptive therapy: A Systematic Review.

BACKGROUND: Osteoporosis is common, affecting more than 20% of women and 6% of men globally over the age of 50 (1). Anti-resorptive drugs, bisphosphonates and denosumab, have been effective treatments for osteoporosis for more than 30 years. Rare complications of anti-resorptive therapy include medication-related osteonecrosis of the jaw and atypical femur fractures (AFF). The American Society for Bone and Mineral Research (ASBMR) proposed a case definition for these atypical femoral fractures in 2010, which was updated in 2013. However, atypical fractures at non-classical sites have been increasingly described. AIMS: We aimed to systematically identify atypical fracture cases, excluded from the ASBMR AFF case definition in patients receiving anti-resorptive medication for longer than three years. METHODS: A structured search of electronic databases, including PubMed, Medline (Ovid), Embase (Ovid), Cochrane and Web of Sciences, and hand-searching of conference abstracts was undertaken. All full-text articles written in English describing an atypical fracture in patients (aged >18 years) and receiving anti-resorptive medication for >3 years were included, with data extracted and analysed by two independent reviewers. RESULTS: Sixty-six articles were identified, describing 151 cases of atypical fractures in 114 individuals. The most frequent fracture site was the ulna, followed by the tibia. All patients were taking anti-resorptive treatment prior to or at the time of fracture, most frequently alendronate monotherapy (44%). Most commonly, fractures were transverse in nature (95%), following minimal or no trauma (96%), non-comminuted (98%) with cortical thickening of the surrounding bone (69%). Anti-resorptive treatment was ceased following atypical fracture in the majority (89%). CONCLUSIONS: Atypical fractures are rare and should not deter physicians from appropriate anti-resorptive therapy for osteoporosis. However, clinicians should be alert to their presence, at additional sites to the femur. An update of the current ASBMR AFF case definition to include other skeletal sites could be timely.

Bisphosphonates and denosumab, anti-resorptive medications, have been effective treatments for osteoporosis for more than 30 years. Rare but serious side effects of these therapies include medication-related osteonecrosis of the jaw and atypical femur (thigh bone) fractures. Increasingly however, atypical fractures at non-classical sites have been described. To address this, we systemically reviewed published cases of atypical fractures at sites other than the femur. We identified 151 cases of atypical fractures in 114 individuals. The most frequent site was the ulna, followed by the tibia. All patients were taking anti-resorptive medication prior to or at the time of fracture, most frequently alendronate (44%). Most commonly, fractures were transverse in nature (95%), following minimal or no trauma (96%), non-comminuted (98%) with cortical thickening of the surrounding bone (69%). Although rare, clinicians should be alert to the presence of atypical fractures at sites additional to the femur. If confirmed to be an atypical fracture in the setting of anti-resorptive therapy, we recommend considering cessation of anti-resorptive treatment, limit weight-bearing, consider surgical management and manage their underlying osteoporosis.

Intensive training programme improves handwriting in a community cohort of people with Parkinson's disease.

BACKGROUND: People with Parkinson's disease (PwP) often report problems with their handwriting before they receive a formal diagnosis. Many PwP suffer from deteriorating handwriting throughout their illness, which has detrimental effects on many aspects of their quality of life. AIMS: To assess a 6-week online training programme aimed at improving handwriting of PwP. METHODS: Handwriting samples from a community-based cohort of PwP (n = 48) were analysed using systematic detection of writing problems (SOS-PD) by two independent raters, before and after a 6-week remotely monitored physiotherapy-led training programme. Inter-rater variability on multiple measures of handwriting quality was analysed. The handwriting data was analysed using pre-/post-design in the same individuals. Multiple aspects of the handwriting samples were assessed, including writing fluency, transitions between letters, regularity in letter size, word spacing, and straightness of lines. RESULTS: Analysis of inter-rater reliability showed high agreement for total handwriting scores and letter size, as well as speed and legibility scores, whereas there were mixed levels of inter-rater reliability for other handwriting measures. Overall handwriting quality (p = 0.001) and legibility (p = 0.009) significantly improved, while letter size (p = 0.012), fluency (p = 0.001), regularity of letter size (p = 0.009), and straightness of lines (p = 0.036) were also enhanced. CONCLUSIONS: The results of this study show that this 6-week intensive remotely-monitored physiotherapy-led handwriting programme improved handwriting in PwP. This is the first study of its kind to use this tool remotely, and it demonstrated that the SOS-PD is reliable for measuring handwriting in PwP.

The Specialist Treatment of Inpatients: Caring for Diabetes in Surgery (STOIC-D Surgery) Trial: A Randomized Controlled Trial of Early Intervention With an Electronic Specialist-Led Model of Diabetes Care.

OBJECTIVE: To investigate the effect of early intervention with an electronic specialist-led "proactive" model of care on glycemic and clinical outcomes. RESEARCH DESIGN AND METHODS: The Specialist Treatment of Inpatients: Caring for Diabetes in Surgery (STOIC-D Surgery) randomized controlled trial was performed at the Royal Melbourne Hospital. Eligible participants were adults admitted to a surgical ward during the study with either known diabetes or newly detected hyperglycemia (at least one random blood glucose result ≥11.1 mmol/L). Participants were randomized 1:1 to standard diabetes care or the intervention consisting of an early consult by a specialist inpatient diabetes team using electronic tools for patient identification, communication of recommendations, and therapy intensification. The primary outcome was median patient-day mean glucose (PDMG). The key secondary outcome was incidence of health care-associated infection (HAI). RESULTS: Between 12 February 2021 and 17 December 2021, 1,371 admissions met inclusion criteria, with 680 assigned to early intervention and 691 to standard diabetes care. Baseline characteristics were similar between groups. The early intervention group achieved a lower median PDMG of 8.2 mmol/L (interquartile range [IQR] 6.9-10.0 mmol/L) compared with 8.6 mmol/L (IQR 7.2-10.3 mmol/L) in the control group for an estimated difference of -0.3 mmol/L (95% CI -0.4 to -0.2 mmol/L, P < 0.0001). The incidence of HAI was lower in the intervention group (77 [11%] vs. 110 [16%]), for an absolute risk difference of -4.6% (95% CI -8.2 to -1.0, P = 0.016). CONCLUSIONS: In surgical inpatients, early diabetes management intervention with an electronic specialist-led diabetes model of care reduces glucose and HAI.

Hypervitaminosis D Secondary to a CYP24A1 Loss-of-Function Mutation: An Unusual Cause of Hypercalcemia in Two Siblings.

Hypervitaminosis D as a cause of hypercalcemia may be due to vitamin D intoxication, granulomatous diseases, or abnormalities of vitamin D metabolism. The CYP24A1 gene encodes for the 24-hydroxylase enzyme, which is responsible for the catabolism of 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D). Mutations in CYP24A1 can result in elevated 1,25(OH)2D causing parathyroid hormone (PTH)-independent hypercalcemia, hypercalciuria, nephrolithiasis, and nephrocalcinosis. We present the cases of two siblings exhibiting hypercalcemia secondary to a CYP24A1 loss-of-function mutation. Case 1 presented initially with PTH-dependent hypercalcemia, with localization of a left upper parathyroid adenoma on parathyroid technetium sestamibi (99mTc-MIBI) uptake study. Despite parathyroidectomy (180 mg adenoma), hypercalcemia, hypercalciuria, and low normal PTH levels persisted. A repeat parathyroid 99mTc-MIBI uptake study localized a second adenoma and a right inferior parathyroidectomy was performed (170 mg adenoma). PTH subsequently became undetectable, however hypercalcemia and hypercalciuria persisted. A new presentation of PTH-independent hypercalcemia found to be secondary to a CYP24A1 loss-of-function mutation in his sibling, Case 2, signaled the underlying cause. Cascade testing confirmed both siblings were homozygous for the pathogenic variant c.1186C>T, p.Arg396Trp (R396W) of CYP24A1 (NM_000782.5). In clinical practice CYP24A1 loss-of-function mutations should be considered in patients presenting with PTH-independent hypercalcemia, hypercalciuria, and 1,25(OH)2D levels in the upper normal or elevated range. Although in our case assays of 24,25(OH)2D were not available, calculation of the 25(OH)D:24,25(OH)2D ratio can assist in the diagnostic process. Possible treatments to manage the risk of hypercalcemia in patients with a CYP24A1 loss-of-function mutation include avoidance of vitamin D oversupplementation and excessive sun exposure. Hydration and bisphosphonate therapy can be useful in managing the hypercalcemia. Although not utilized in our cases, treatment with ketoconazole, fluconazole, and rifampicin have been described as potential therapeutic options. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Pak2 Regulation of Nrf2 Serves as a Novel Signaling Nexus Linking ER Stress Response and Oxidative Stress in the Heart.

Endoplasmic Reticulum (ER) stress and oxidative stress have been highly implicated in the pathogenesis of cardiac hypertrophy and heart failure (HF). However, the mechanisms involved in the interplay between these processes in the heart are not fully understood. The present study sought to determine a causative link between Pak2-dependent UPR activation and oxidative stress via Nrf2 regulation under pathological ER stress. We report that sustained ER stress and Pak2 deletion in cardiomyocytes enhance Nrf2 expression. Conversely, AAV9 mediated Pak2 delivery in the heart leads to a significant decrease in Nrf2 levels. Pak2 overexpression enhances the XBP1-Hrd1 UPR axis and ameliorates tunicamycin induced cardiac apoptosis and dysfunction in mice. We found that Pak2 deletion and altered proteostasis render Nrf2 detrimental by switching from its antioxidant role to renin-angiotensin aldosterone system (RAAS) gene regulator. Mechanistically, Pak2 mediated Hrd1 expression targets Nrf2 for ubiquitination and degradation thus preventing its aberrant activation. Moreover, we find a significant increase in Nrf2 with a decrease in Pak2 in human myocardium of dilated heart disease. Using human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we find that Pak2 is able to ameliorate Nrf2 induced RAAS activation under ER stress. These findings demonstrate that Pak2 is a novel Nrf2 regulator in the stressed heart. Activation of XBP1-Hrd1 is attributed to prevent ER stress-induced Nrf2 RAAS component upregulation. This mechanism explains the functional dichotomy of Nrf2 in the stressed heart. Thus, Pak2 regulation of Nrf2 homeostasis may present as a potential therapeutic route to alleviate detrimental ER stress and heart failure.

Regulation of Long Non-coding RNAs and MicroRNAs in Heart Disease: Insight Into Mechanisms and Therapeutic Approaches.

Cardiovascular disease is the leading cause of mortality worldwide and there is an increasing need to identify new therapeutic targets that could be used to prevent or treat these diseases. Due to recent scientific advances, non-coding RNAs are widely accepted as important regulators of cellular processes, and the identification of an axis of interaction between long non-coding RNAs (lncRNAs) and micro RNAs (miRNAs) has provided another platform through which cardiovascular disease could be targeted therapeutically. Increasing evidence has detailed the importance of these non-coding RNAs, both individually and in an axis of regulation, in the processes and diseases involving the heart. However, further investigation into the consequences of targeting this mechanism, as well as refinement of how the system is targeted, are required before a treatment can be provided in clinic. This level of genomic regulation provides an exciting potential novel therapeutic strategy for the treatment of cardiovascular disease.

Targeting mir128-3p alleviates myocardial insulin resistance and prevents ischemia-induced heart failure.

Myocardial insulin resistance contributes to heart failure in response to pathological stresses, therefore, a therapeutic strategy to maintain cardiac insulin pathways requires further investigation. We demonstrated that insulin receptor substrate 1 (IRS1) was reduced in failing mouse hearts post-myocardial infarction (MI) and failing human hearts. The mice manifesting severe cardiac dysfunction post-MI displayed elevated mir128-3p in the myocardium. Ischemia-upregulated mir128-3p promoted Irs1 degradation. Using rat cardiomyocytes and human-induced pluripotent stem cell-derived cardiomyocytes, we elucidated that mitogen-activated protein kinase 7 (MAPK7, also known as ERK5)-mediated CCAAT/enhancer-binding protein beta (CEBPß) transcriptionally represses mir128-3p under hypoxia. Therapeutically, functional studies demonstrated gene therapy-delivered cardiac-specific MAPK7 restoration or overexpression of CEBPß impeded cardiac injury after MI, at least partly due to normalization of mir128-3p. Furthermore, inhibition of mir128-3p preserved Irs1 and ameliorated cardiac dysfunction post-MI. In conclusion, we reveal that targeting mir128-3p mitigates myocardial insulin resistance, thereafter slowing down the progression of heart failure post-ischemia.

Mitochondrial function in the heart: the insight into mechanisms and therapeutic potentials.

Mitochondrial dysfunction is considered as a crucial contributory factor in cardiac pathology. This has highlighted the therapeutic potential of targeting mitochondria to prevent or treat cardiac disease. Mitochondrial dysfunction is associated with aberrant electron transport chain activity, reduced ATP production, an abnormal shift in metabolic substrates, ROS overproduction and impaired mitochondrial dynamics. This review will cover the mitochondrial functions and how they are altered in various disease conditions. Furthermore, the mechanisms that lead to mitochondrial defects and the protective mechanisms that prevent mitochondrial damage will be discussed. Finally, potential mitochondrial targets for novel therapeutic intervention will be explored. We will highlight the development of small molecules that target mitochondria from different perspectives and their current progress in clinical trials. LINKED ARTICLES: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc.

The motor and cognitive features of Parkinson's disease in patients with concurrent Gaucher disease over 2 years: a case series.

We report the cognitive features and progression of Parkinson's disease (PD) in five patients with concurrent Gaucher disease. The patients presented at an earlier age than patients with sporadic PD, as previously noted by others; but in contrast to many previous reports, our patients followed a variable clinical course. While two patients developed early cognitive deficits and dementia, three others remained cognitively intact over the follow-up period. Thus, in this small case series, PD in the context of GD more closely resembles idiopathic PD in terms of its clinical heterogeneity in contrast to PD associated with GBA heterozygote mutations.

The long-term quality of life outcomes in adolescents with Hirschsprung disease.

BACKGROUND: Postoperative outcomes for Hirschsprung disease (HD) remain variable, with many patients affected by constipation and/or fecal incontinence. The long-term impact upon quality of life (QoL) for HD patients is unclear. We measured long-term QoL outcomes in adolescents with HD using validated questionnaires. METHODS: Patients with HD, managed at a large tertiary pediatric institution between 1997 and 2004, were identified. Patients and/or their proxy completed validated questionnaires. Results were compared with published healthy population controls. Two questionnaires assessed QoL: Pediatric Quality of Life Inventory (PedsQL) and Fecal Incontinence and Constipation Quality of Life (FICQOL). Three measures assessed functional outcomes: Baylor Continence Scale, Cleveland Clinic Constipation Scoring System, and Vancouver Dysfunctional Elimination Symptom Survey. RESULTS: Interviews were completed for 58 (70% response rate) patients [M:F, 49:9; median age, 14.5 years (11.1-18.7)]. No significant differences were found in general QoL scores between patients and healthy controls (84.84 versus 81.49, p = 0.28). Disease-specific questionnaires revealed reduced QoL in patients and families, with 17% of parents reporting the bowel dysfunction stopped their child from socializing and 47% of parents experiencing some degree of anxiety/depression regarding their child's bowel condition. Fecal incontinence (r = -0.59, p < 0.01), constipation (r = -0.36, p = 0.01), and dysfunctional elimination (r = -0.59, p < 0.01) all negatively correlated with QoL scores. CONCLUSIONS: In this study, generic QoL in the adolescent HD population was comparable to healthy populations. However, children with HD have ongoing bowel dysfunction which negatively impacts upon their QoL. LEVEL OF EVIDENCE: Prognosis study:- level II (prospective cohort study).

Quality of life outcomes in children with Hirschsprung disease.

BACKGROUND: Morbidity following repair of Hirschsprung disease (HD) is common. However, quality of life (QoL) results focused on HD children are contradictory. We aimed to measure QoL outcomes in HD children using validated questionnaires. METHODS: Patients with HD, managed at a large tertiary pediatric institution between 2004 and 2013, were identified. Parents completed validated questionnaires. Results were compared with published healthy population controls. QoL outcomes were measured using Pediatric Quality of Life (PedsQL) and Fecal Incontinence and Constipation Quality of Life (FIC QOL). Functional outcomes were assessed using Baylor Continence Scale, Cleveland Clinic Constipation Scoring System, and Vancouver Dysfunctional Elimination Syndrome Survey. RESULTS: Parents of 60 HD patients [M:F 49:11; median age 6.4years (2.3-10.9)] were interviewed (59% participation). The majority (47/60, 78%) had rectosigmoid disease. There was significant reduction in psychosocial (social and emotional) QoL compared with healthy children (p=0.03). Psychosocial functioning was affected by increasing age (r=-2.72, p<0.001), fecal incontinence (r=-0.475, p=0.007), constipation (r=-1.58, p=0.006), and dysfunctional elimination (r=-2.94, p=0.004). Fecal incontinence also reduced physical functioning QoL (r=-0.306, p=0.007). Children with HD had significantly higher levels of fecal incontinence (p<0.01). CONCLUSIONS: We have demonstrated that HD children have significant reductions in psychosocial QoL and functional outcomes. LEVEL OF EVIDENCE: Prognosis Study - Level II (Prospective cohort study).

Dermal fibroblasts from patients with Parkinson's disease have normal GCase activity and autophagy compared to patients with PD and GBA mutations.

Background: Recently, the development of Parkinson's disease (PD) has been linked to a number of genetic risk factors, of which the most common is glucocerebrosidase (GBA) mutations. Methods: We investigated PD and Gaucher Disease (GD) patient derived skin fibroblasts using biochemistry assays. Results: PD patient derived skin fibroblasts have normal glucocerebrosidase (GCase) activity, whilst patients with PD and GBA mutations have a selective deficit in GCase enzyme activity and impaired autophagic flux. Conclusions: This data suggests that only PD patients with a GBA mutation have altered GCase activity and autophagy, which may explain their more rapid clinical progression.

REST suppression mediates neural conversion of adult human fibroblasts via microRNA-dependent and -independent pathways.

Direct conversion of human fibroblasts into mature and functional neurons, termed induced neurons (iNs), was achieved for the first time 6 years ago. This technology offers a promising shortcut for obtaining patient- and disease-specific neurons for disease modeling, drug screening, and other biomedical applications. However, fibroblasts from adult donors do not reprogram as easily as fetal donors, and no current reprogramming approach is sufficiently efficient to allow the use of this technology using patient-derived material for large-scale applications. Here, we investigate the difference in reprogramming requirements between fetal and adult human fibroblasts and identify REST as a major reprogramming barrier in adult fibroblasts. Via functional experiments where we overexpress and knockdown the REST-controlled neuron-specific microRNAs miR-9 and miR-124, we show that the effect of REST inhibition is only partially mediated via microRNA up-regulation. Transcriptional analysis confirmed that REST knockdown activates an overlapping subset of neuronal genes as microRNA overexpression and also a distinct set of neuronal genes that are not activated via microRNA overexpression. Based on this, we developed an optimized one-step method to efficiently reprogram dermal fibroblasts from elderly individuals using a single-vector system and demonstrate that it is possible to obtain iNs of high yield and purity from aged individuals with a range of familial and sporadic neurodegenerative disorders including Parkinson's, Huntington's, as well as Alzheimer's disease.

The Genetic Basis of Cognitive Impairment and Dementia in Parkinson's Disease.

Cognitive dysfunction is a common feature of Parkinson's disease (PD) with mild cognitive impairment affecting around a quarter of patients in the early stages of their disease, and approximately half developing dementia by 10 years from diagnosis. However, the pattern of cognitive impairments and their speed of evolution vary markedly between individuals. While some of this variability may relate to extrinsic factors and comorbidities, inherited genetic heterogeneity is also known to play an important role. A number of common genetic variants have been identified, which contribute to cognitive function in PD, including variants in catechol-O-methyltransferase, microtubule-associated protein tau, and apolipoprotein E. Furthermore, rarer mutations in glucocerebrosidase and α-synuclein and are strongly associated with dementia risk in PD. This review explores the functional impact of these variants on cognition in PD and discusses how such genotype-phenotype associations provide a window into the mechanistic basis of cognitive heterogeneity in this disorder. This has consequent implications for the development of much more targeted therapeutic strategies for cognitive symptoms in PD.