Atypical fractures at non-classical sites associated with anti-resorptive therapy: a systematic review.

Osteoporosis is common, affecting more than 20% of women and 6% of men globally over the age of 50. 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 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.

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.

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.

Hypervitaminosis D Secondary to a 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 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 can result in elevated 1,25(OH)2D causing parathyroid hormone (PTH)-independent hypercalcemia, hypercalciuria, nephrolithiasis, and nephrocalcinosis.

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.

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.

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 Nrf2 regulation under pathological ER stress.

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.

Targeting 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 in the myocardium.

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.

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.

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.

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.

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

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. We investigated PD and Gaucher Disease (GD) patient derived skin fibroblasts using biochemistry assays. 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.

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.

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.

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.

Novel Nut and Bolt Task Quantifies Motor Deficits in Premanifest and Manifest Huntington's Disease.

Background: We investigated the use of a simple novel nut and bolt task in premanifest and manifest Huntington's disease (HD) patients to detect and quantify motor impairments at all stages of the disease.

Methods: Premanifest HD (n=24), manifest HD (n=27) and control (n=32) participants were asked to screw a nut onto a bolt in one direction, using three different sized bolts with their left and right hand in turn.

Results: We identified some impairments at all stages of HD and in the premanifest individuals, deficits in the non-dominant hand correlated with disease burden scores.

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.

The Addenbrooke's Cognitive Examination-Revised accurately detects cognitive decline in Huntington's disease.

Cognitive features, which begin before manifestation of the motor features, are an integral part of Huntington's disease and profoundly affect quality of life. A number of neuropsychological batteries have been used to assess this aspect of the condition, many of which are difficult to administer and time consuming, especially in advanced disease. We, therefore, investigated a simple and practical way to monitor cognition using the Addenbrooke's Cognitive Examination-Revised (ACE-R) in 126 manifest Huntington's disease patients, 28 premanifest gene carriers and 21 controls.