Sublithospheric diamond ages and the supercontinent cycle.

Subduction related to the ancient supercontinent cycle is poorly constrained by mantle samples. Sublithospheric diamond crystallization records the release of melts from subducting oceanic lithosphere at 300-700 km depths1,2 and is especially suited to tracking the timing and effects of deep mantle processes on supercontinents. Here we show that four isotope systems (Rb-Sr, Sm-Nd, U-Pb and Re-Os) applied to Fe-sulfide and CaSiO3 inclusions within 13 sublithospheric diamonds from Juína (Brazil) and Kankan (Guinea) give broadly overlapping crystallization ages from around 450 to 650 million years ago. The intracratonic location of the diamond deposits on Gondwana and the ages, initial isotopic ratios, and trace element content of the inclusions indicate formation from a peri-Gondwanan subduction system. Preservation of these Neoproterozoic-Palaeozoic sublithospheric diamonds beneath Gondwana until its Cretaceous breakup, coupled with majorite geobarometry3,4, suggests that they accreted to and were retained in the lithospheric keel for more than 300 Myr during supercontinent migration. We propose that this process of lithosphere growth-with diamonds attached to the supercontinent keel by the diapiric uprise of depleted buoyant material and pieces of slab crust-could have enhanced supercontinent stability.

Quantitative Gait and Balance Outcomes for Ataxia Trials: Consensus Recommendations by the Ataxia Global Initiative Working Group on Digital-Motor Biomarkers.

With disease-modifying drugs on the horizon for degenerative ataxias, ecologically valid, finely granulated, digital health measures are highly warranted to augment clinical and patient-reported outcome measures. Gait and balance disturbances most often present as the first signs of degenerative cerebellar ataxia and are the most reported disabling features in disease progression. Thus, digital gait and balance measures constitute promising and relevant performance outcomes for clinical trials.This narrative review with embedded consensus will describe evidence for the sensitivity of digital gait and balance measures for evaluating ataxia severity and progression, propose a consensus protocol for establishing gait and balance metrics in natural history studies and clinical trials, and discuss relevant issues for their use as performance outcomes.

Interrater Reliability of the Scale for the Assessment and Rating of Ataxia, Berg Balance Scale, and Functional Independence Measure Motor Domain in Individuals With Hereditary Cerebellar Ataxia.

OBJECTIVE: To determine the interrater reliability of the Scale for the Assessment and Rating of Ataxia (SARA), Berg Balance Scale (BBS), and motor domain of the FIM (m-FIM) administered by physiotherapists in individuals with a hereditary cerebellar ataxia (HCA). DESIGN: Participants were assessed by 1 of 4 physiotherapists. Assessments were video-recorded and the remaining 3 physiotherapists scored the scales for each participant. Raters were blinded to each other's scores. SETTING: Assessments were administered at 3 clinical locations in separate states in Australia. PARTICIPANTS: Twenty-one individuals (mean age=47.63 years; SD=18.42; 13 male and 8 female) living in the community with an HCA were recruited (N=21). MAIN OUTCOME MEASURES: Total and single-item scores of the SARA, BBS, and m-FIM were examined. The m-FIM was conducted by interview. RESULTS: Intraclass coefficients (2,1) for the total scores of the m-FIM (0.92; 95% confidence interval [CI], 0.85-0.96), SARA (0.92; 95% CI, 0.86-0.96), and BBS (0.99; 95% CI, 0.98-0.99) indicated excellent interrater reliability. However, there was inconsistent agreement with the individual items, with SARA item 5 (right side) and item 7 (both sides) demonstrating poor interrater reliability and items 1 and 2 demonstrating excellent reliability. CONCLUSIONS: The m-FIM (by interview), SARA, and BBS have excellent interrater reliability for use when assessing individuals with an HCA. Physiotherapists could be considered for administration of the SARA in clinical trials. However, further work is required to improve the agreement of the single-item scores and to examine the other psychometric properties of these scales.

Instrumented Objective Clinical Examination of Cerebellar Ataxia: the Upper and Lower Limb-a Review.

Cerebellar dysfunction results in impairments in co-ordination or 'ataxia'. Bedside examination of cerebellar function has changed little since the early nineteenth century with the exception being the oculomotor examination which has become instrumented. Otherwise, competence and confidence in performing the clinical assessment relies heavily on the skill and experience of the clinician. Potentially, instrumented objective measurement will more accurately assess the severity of ataxia and the changes brought about by advancing therapies in pharmaceutical trials and in rehabilitation intervention. This study describes instrumented versions of several bedside tests of cerebellar function, including rhythmic tapping of the hand (RTH), finger-nose test (FNT), dysdiadochokinesia (DDK), ramp tracking (RMT), ballistic tracking (BT), rhythmic tapping of the foot (RTF) and the heel shin (HST) examination which were validated against scores from Ataxia Rating Scales (ARS) such as the Scale of Assessment and Rating of Ataxia (SARA). While all of the instrumented tests accurately distinguished between ataxic subjects and controls, there was a difference in performance, with the best four performing upper limb tests being RTH, FNT, DDK and BT. A combination of BT plus RTH provided the best correlation with the SARA and outperformed a combination of all the bedside tests (Spearman 0.8; p < 0.001 compared to 0.68; p < 0.001 for the combined set) in identifying the presence and severity of ataxia. This indicates that there is redundancy in the information provided by the bedside tests and that adding other tests to BT plus RTH does not add accuracy to the assessment of ataxia. This analysis highlighted the need for metrics that could be generalised to each of the assessments of ataxia, so, in turn, domains of stability, timing, accuracy and rhythmicity (STAR domains) were developed and compared to the SARA. The STAR criteria could potentially influence the future of instrumented assessment in CA and pave the way for further research into the objective measurement of the cerebellar examination.

The Responsiveness of Gait and Balance Outcomes to Disease Progression in Friedreich Ataxia.

To identify gait and balance measures that are responsive to change during the timeline of a clinical trial in Friedreich ataxia (FRDA), we administered a battery of potential measures three times over a 12-month period. Sixty-one ambulant individuals with FRDA underwent assessment of gait and balance at baseline, 6 months and 12 months. Outcomes included GAITRite® spatiotemporal gait parameters; Biodex Balance System Postural Stability Test (PST) and Limits of Stability; Berg Balance Scale (BBS); Timed 25-Foot Walk Test; Dynamic Gait Index (DGI); SenseWear MF Armband step and energy activity; and the Friedreich Ataxia Rating Scale Upright Stability Subscale (FARS USS). The standardised response mean (SRM) or correlation coefficients were reported as effect size indices for comparison of internal responsiveness. Internal responsiveness was also analysed in subgroups. SenseWear Armband daily step count had the largest effect size of all the variables over 6 months (SRM = -0.615), while the PST medial-lateral index had the largest effect size (SRM = 0.829) over 12 months. The FARS USS (SRM = 0.824) and BBS (SRM = -0.720) were the only outcomes able to detect change over 12 months in all subgroups. The DGI was the most responsive outcome in children, detecting a mean change of -2.59 (95% CI -3.52 to -1.66, p < 0.001, SRM = -1.429). In conclusion, the FARS USS and BBS are highly responsive and can detect change in a wide range of ambulant individuals with FRDA. However, therapeutic effects in children may be best measured by the DGI.

Accuracy of Opportunistic Bone Mineral Density Assessment on Staging Computed Tomography for Gynaecological Cancers.

Background and Objectives: Women with gynecological cancers constitute a high-risk cohort for loss of bone density. International guidance stipulates women undergoing cancer treatments associated with bone loss should have a quantitative assessment of bone density. Access to Dual-energy X-ray Absorptiometry (DXA) is limited. This study aimed to assess the accuracy of opportunistic bone density measurement on staging computed tomography (CT) scans for gynaecological malignancies, in comparison to the gold standard DXA. Materials and Methods: Women with a staging CT scan of the abdomen and pelvis for a new diagnosis of gynecological cancer were recruited. DXA was performed within 6 weeks of treatment for gynaecological cancer. Lumbar bone density was measured by CT attenuation values, in Hounsfield units (HU), of the anterior trabecular region. Correlations between CT and DXA parameters were analysed. Receiver Operating Characteristic(ROC) curves for diagnosis of low bone density and osteoporosis were analysed. Results: Final cohort included 48 of 50 women recruited. There was good diagnostic accuracy for abnormal bone density and osteoporosis, with areas under the ROC curve at L1 of 0.77 (p = 0.002) and 0.80 (p = 0.020) respectively. CT-HU of 170-190 yielded sensitivities of 87-90%, positive predictive values of 75-84% and negative predictive values of 71-75% for the diagnosis of low bone mineral density. CT-HU of 90-110 yielded specificities of 85-93% for the diagnosis of osteoporosis. Moderate correlations were found between CT-HU and both DXA T-scores and diagnostic categories. Conclusions: This is the first study to assess the opportunistic application of CT in the assessment of bone health in women with gynaecological cancer, a cohort at high-risk of osteoporosis. The correlation between bone density assessment in CT-HU and DXA, and strong AUC values for the diagnosis of low bone density (0.77) and osteoporosis (0.80) support this pragmatic solution in resolving the care-gap in cancer treatment-induced bone loss, often associated with poor access to DXA.

An ultrasound assessment of gastric emptying following tea with milk in pregnancy: A randomised controlled trial.

BACKGROUND: Peri-operative fasting guidelines allow clear fluids including tea without milk to be consumed up to 2 h before surgery. Recent evidence has shown that a modest amount of milk consumed with clear fluids does not significantly slow gastric emptying. OBJECTIVES: The aim of this study was to compare the gastric emptying of tea with milk versus water using ultrasonography in fasted pregnant patients. DESIGN: A randomised controlled trial quantifying gastric emptying in two groups using ultrasonography by an operator blinded to the group allocation. SETTING: Department of Anaesthesia and Peri-operative Medicine, Coombe Women and Infants University Hospital, Dublin. The study was conducted between October 2018 and June 2019. PARTICIPANTS: Total 50 nonlabouring pregnant women, more than 36 weeks gestation. INTERVENTIONS: After a standard overnight fast, women were randomised to either 250 ml of water or 250 ml of tea with milk. All patients underwent a gastric ultrasound assessment at regular intervals for 2 h after consumption of their drink. MAIN OUTCOME MEASURE: The primary outcome was the difference in gastric antrum cross-sectional area (CSA) at 2 h. RESULTS: A total of 50 women were recruited to the study. There was no significant difference in the median [IQR] gastric antrum CSA in either group at 2 h: 3.2 cm [2.3 to 3.7] vs. 3.1 cm [2.6 to 3.9]; P = 0.720. The gastric antrum CSA had returned to its baseline measurement in both groups by 90 min. CONCLUSION: The change of gastric antrum CSA after 250 ml of tea with milk is similar to a corresponding volume of water in fasted pregnant patients. This study could help inform future peri-operative fasting guidelines regarding the use of a modest volume of milk with clear fluids. TRIAL REGISTRY NUMBER: NCT03694509 ClinicalTrials.gov.

Can rehabilitation improve the health and well-being in Friedreich's ataxia: a randomized controlled trial?

OBJECTIVE: To determine the effectiveness of a six-week rehabilitation programme followed by a home exercise programme for Friedreich's ataxia. DESIGN: Randomized, delayed-start control single-blind trial. SETTING: Outpatient rehabilitation centre. SUBJECTS: Ambulant or non-ambulant individuals with Friedreich's ataxia. INTERVENTION: Participants were randomized to a six-week outpatient rehabilitation programme, immediately (intervention group) or after a six-week delayed-start (control group). The rehabilitation was followed by a six-week home exercise programme. MAIN MEASURES: The primary outcome was the Functional Independence Measure. Other measures included the Friedreich Ataxia Impact Scale and the Friedreich Ataxia Rating Scale. Outcomes were administered at baseline, 6, 12 and 18 weeks. RESULTS: Of 159 individuals screened, 92 were excluded and 48 declined to participate. A total of 19 participants were enrolled in the study. There was no significant difference in Functional Independence Measure change from baseline to six weeks in the intervention group (mean ± standard deviation, 2.00 ± 3.16) as compared to the control group (0.56 ± 4.06). Change in the Friedreich Ataxia Impact Scale body movement subscale indicated a significant improvement in health and well-being in the intervention group compared to the control group ( P = 0.003). Significant within-group improvements in the Friedreich Ataxia Impact Scale and the motor domain of the Functional Independence Measure post-rehabilitation were not sustained post-home exercise programme. CONCLUSION: Our study indicates that rehabilitation can improve health and well-being in individuals with Friedreich's ataxia; however, a larger study is required to have sufficient power to detect a significant change in the most sensitive measure of function, the motor domain of the Functional Independence Measure.

Progress in the treatment of Friedreich ataxia.

Friedreich ataxia (FRDA) is a progressive neurological disorder affecting approximately 1 in 29,000 individuals of European descent. At present, there is no approved pharmacological treatment for this condition however research into treatment of FRDA has advanced considerably over the last two decades since the genetic cause was identified. Current proposed treatment strategies include decreasing oxidative stress, increasing cellular frataxin, improving mitochondrial function as well as modulating frataxin controlled metabolic pathways. Genetic and cell based therapies also hold great promise. Finally, physical therapies are being explored as a means of maximising function in those affected by FRDA.

Sensitivity of spatiotemporal gait parameters in measuring disease severity in Friedreich ataxia.

Friedreich ataxia (FRDA) is an autosomal recessive disease with gait ataxia being the main source of morbidity. Mobility progressively declines, from initial symptom onset at approximately 10-15 years of age to being unable to ambulate 10-15 years later. Here, we sought to investigate the relationship between spatiotemporal gait parameters and clinical markers of disease severity. Thirteen people with FRDA walked along an 8.3-m GAITRite® mat six times each at their preferred fast and slow speeds. Relationships between spatiotemporal gait parameters and a range of clinical and disease characteristics were examined. Significant correlations were found between spatiotemporal gait characteristics at each of the walking speeds and Friedreich Ataxia Rating Scale (FARS) score and disease duration. During the fast-walking condition, gait speed and cadence decreased with an increase in disease duration and the FARS score. GAA1 repeat expansion negatively correlated with double-support percentage of the gait cycle in all speed conditions demonstrating a relationship between the genetic mutation and compensatory strategies for impaired dynamic balance. In all speed conditions, there were correlations between a range of spatiotemporal gait characteristics and the timed 25-ft walk test, a well-established measure of gait mobility. These findings suggest that spatiotemporal gait parameters are a sensitive measure of gait decline in individuals with FRDA and should be considered for inclusion in intervention studies whilst participants are still ambulant.

Adapting to higher demands: using innovative methods to treat infants presenting with torticollis and plagiocephaly.

PURPOSE: Referrals for torticollis/plagiocephaly have increased dramatically because of "Back to Sleep" campaigns and front-line staff becoming more proficient at recognition and referral to physiotherapy. These infants generally respond well to early intervention so longer waitlists raise concern about clinical outcomes due to delay. METHODS: Therapists developed a group-based, team service delivery model based on best practices in individual treatment programs. The program was implemented and evaluated for assessment and treatment of infants presenting with these conditions, including caregiver satisfaction. RESULTS: Compared with individual treatment, the group format enabled therapists to increase capacity to serve this population by 70%, with equivalent quality and achievement of discharge criteria, as well as a modest service cost saving per child. Caregiver questionnaires indicate satisfaction with the service. CONCLUSIONS: Group service delivery is a cost-effective and efficient way to manage increased referrals for torticollis/plagiocephaly while maintaining comparable treatment outcomes. VIDEO ABSTRACT: For more insights from the authors, see Supplemental Digital Content 1, available at http://links.lww.com/PPT/A64.

Myelin oligodendrocyte glycoprotein reactive Th17 cells drive Janus Kinase 1 dependent transcriptional reprogramming in astrocytes and alter cell surface cytokine receptor profiles during experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an autoimmune demyelinating disease affecting the central nervous system (CNS). T helper (Th) 17 cells are involved in the pathogenesis of MS and its animal model of experimental autoimmune encephalomyelitis (EAE) by infiltrating the CNS and producing effector molecules that engage resident glial cells. Among these glial cells, astrocytes have a central role in coordinating inflammatory processes by responding to cytokines and chemokines released by Th17 cells. In this study, we examined the impact of pathogenic Th17 cells on astrocytes in vitro and in vivo. We identified that Th17 cells reprogram astrocytes by driving transcriptomic changes partly through a Janus Kinase (JAK)1-dependent mechanism, which included increased chemokines, interferon-inducible genes, and cytokine receptors. In vivo, we observed a region-specific heterogeneity in the expression of cell surface cytokine receptors on astrocytes, including those for IFN-γ, IL-1, TNF-α, IL-17, TGFß, and IL-10. Additionally, these receptors were dynamically regulated during EAE induced by adoptive transfer of myelin-reactive Th17 cells. This study overall provides evidence of Th17 cell reprogramming of astrocytes, which may drive changes in the astrocytic responsiveness to cytokines during autoimmune neuroinflammation.

WITHDRAWN: Therapeutic ultrasound for treating patellofemoral pain syndrome.

BACKGROUND: Therapeutic ultrasound is one of several rehabilitation interventions suggested for the management of pain due to patellofemoral knee pain syndrome. OBJECTIVES: To assess the effectiveness and side effects of ultrasound therapy for treating patellofemoral knee pain syndrome. SEARCH METHODS: We searched the Cochrane Musculoskeletal Review Group register, Cochrane Field of Physical and Related Therapies register, Cochrane Controlled Trials Register, MEDLINE, EMBASE, HealthSTAR, Sports Discus, CINAHL,and PEDro databases (to December 2000) according to the sensitive search strategy for RCTs designed for the Cochrane Collaboration. The search was complemented with handsearching of the reference lists. Key experts in the area were contacted for any further articles. SELECTION CRITERIA: All randomized controlled trials (RCTs), controlled clinical trials (CCTs), case-control and cohort studies comparing therapeutic ultrasound against placebo or another active intervention in people with patellofemoral pain syndrome were selected according to an a priori protocol. DATA COLLECTION AND ANALYSIS: Two reviewers determined the studies to be included based on a priori inclusion criteria. Data were independently extracted by the same two reviewers and checked by a third reviewer (BS) using a previously developed form. The same two reviewers independently assessed the methodological quality of the RCTs and CCTs using a validated scale. The data analysis was performed using Peto odds ratios. MAIN RESULTS: The search retrieved 85 articles. Of the eight that were potentially relevant, only one RCT, including 53 participants with patellofemoral pain syndrome, was identified for this review. All participants received an exercise program as concurrent therapy. Ultrasound combined with ice massage contrast (n of 13), where n equals the number of participants, was not statistically different from ice massage alone (n = 16) in terms of participant-rated pain relief or quadriceps and hamstring strengthening. In the ultrasound and ice massage group, 46% (6 of 13) reported improved pain relief compared to 31% (4 of 13) in the ice massage alone group. This difference of 15% does not meet international standards for clinically important improvements in osteoarthritis, which is 20%. Side effects were not reported. AUTHORS' CONCLUSIONS: Ultrasound therapy was not shown to have a clinically important effect on pain relief for people with patellofemoral pain syndrome. These conclusions are limited by the poor reporting of the therapeutic application of the ultrasound and low methodological quality of the one trial included. No conclusions can be drawn concerning the use, or non-use, of ultrasound for treating patellofemoral pain syndrome. More well-designed studies are needed.

Modified Recurrence Quantification Analysis for Objective Assessment of Cerebellar Ataxia.

Cerebellar Ataxia (CA) is a neurological condition that affects coordination, balance and speech. Assessing its severity is important for developing effective treatment and rehabilitation plans. Traditional assessment methods involve a clinician instructing a person with ataxia to perform tests and assigning a severity score based on their performance. However, this approach is subjective as it relies on the clinician's experience, and can vary between clinicians. To address this subjectivity, some researchers have developed automated assessment methods using signal processing and data-driven approaches, such as supervised machine learning. These methods still rely on subjective ground truth and can perform poorly in real-world scenarios. This research proposed an alternative approach that uses signal processing to modify recurrence plots and compare the severity of ataxia in a person with CA to a control cohort. The highest correlation score obtained was 0.782 on the back sensor with the feet-apart and eyes-open test. The contributions of the research include modifying the recurrence plot as a measurement tool for assessing CA severity, proposing a new approach to assess severity by comparing kinematic data between people with CA and a control reference group, and identifying the best subtest and sensor position for practical use in CA assessments.

Phosphorylation regulates polarisation of chitin synthesis in Candida albicans.

The ability to undergo polarised cell growth is fundamental to the development of almost all walled organisms. Fungi are characterised by yeasts and moulds, and both cellular forms have been studied extensively as tractable models of cell polarity. Chitin is a hallmark component of fungal cell walls. Chitin synthesis is essential for growth, viability and rescue from many conditions that impair cell-wall integrity. In the polymorphic human pathogen Candida albicans, chitin synthase 3 (Chs3) synthesises the majority of chitin in the cell wall and is localised at the tips of growing buds and hyphae, and at the septum. An analysis of the C. albicans phospho-proteome revealed that Chs3 can be phosphorylated at Ser139. Mutation of this site showed that both phosphorylation and dephosphorylation are required for the correct localisation and function of Chs3. The kinase Pkc1 was not required to target Chs3 to sites of polarised growth. This is the first report demonstrating an essential role for chitin synthase phosphorylation in the polarised biosynthesis of fungal cell walls and suggests a new mechanism for the regulation of this class of glycosyl-transferase enzyme.

Retrospective study of the effects of inpatient rehabilitation on improving and maintaining functional independence in people with Friedreich ataxia.

OBJECTIVES: To determine the effects of inpatient intervention for people with Friedreich ataxia (FRDA), and to identify whether improvements gained were sustained postdischarge. DESIGN: This retrospective observational cohort study comprised people with FRDA admitted to inpatient rehabilitation. SETTING: All participants in the study were referred by a specialist multidisciplinary FRDA clinic to inpatient rehabilitation. PARTICIPANTS: From 2003 until 2010, people (N=29; men, n=17; women, n=12) with FRDA were admitted to rehabilitation, representing 42 admissions. On admission, 9 participants were ambulant and 33 participants were nonambulant. INTERVENTIONS: Each participant was prescribed goal-related therapy on an individual basis by the multidisciplinary team, and this consisted of a range of treatment approaches. MAIN OUTCOME MEASURE: The FIM was used to determine the efficacy of inpatient rehabilitation. RESULTS: Consistent with the progressive nature of the condition, FIM scores, as measured on an annual basis preintervention, declined over time. However, FIM scores increased by a mean of 8.5 points during periods of inpatient rehabilitation and continued to increase by a mean of 2.0 points during the period immediately after rehabilitation. Results demonstrate these increases during and immediately after inpatient rehabilitation were significant (P<.001). CONCLUSIONS: To the best of our knowledge, this study provides the first evidence that a period of inpatient rehabilitation reverses or halts the downward decline in function for people with FRDA. The benefits from this intervention continued during the period immediately after inpatient rehabilitation, indicating that these gains are more than just short-term achievements. Further exploration of intensity, type, and length of rehabilitation is required to ensure that the most appropriate rehabilitation is provided.

Socio-environmental models of allied health disability support: an exploration of narrative experiences in the Australian National Disability and Insurance Scheme.

Objective The primary aims of this study were to explore: (1) manifestations of socio-environmental models of allied health support provision in the disability sector; and (2) narrative experiences of individual allied health professionals in the disability sector. Methods A narrative qualitative study using interviews from a purposive sample of two allied health professionals working in the disability sector explored manifestations of socio-environmental models of allied health support provision and their experiences from case examples. The key informants had more than 10 years of experience in the disability support services setting. Results Seven key themes exploring manifestations of socio-environmental models of allied health professional practice in the disability sector emerged: (1) dignity of risk; (2) models of care; (3) considerations when working in the supported person's environment; (4) goal-oriented work; (5) informed choice and informed consent; (6) reactive and flexible plans; and (7) training and education role. Conclusions Socio-environmental models of allied health support provision in the disability sector focus on empowering people with disability to achieve their goals. This may require displacement of cultural norms within the allied health professions. What is known about the topic? Socio-environmental models of allied health support provision in the disability sector focus on empowering people with disability to achieve their goals. What does this paper add? Displacement of cultural norms within the allied health professions may be needed to promote positive risk taking. Challenges for allied health professionals remain in navigating conflicting goals between clients and family members, empowering informed choice and consent, and working in uncontrolled environments. What are the implications for practitioners? Adopting training and education roles for clients, family members and carers when implementing National Disability and Insurance Scheme plans may represent one of the many pragmatic and flexible approaches to achieve people's goals.

Clinical management guidelines for Friedreich ataxia: best practice in rare diseases.

BACKGROUND: Individuals with Friedreich ataxia (FRDA) can find it difficult to access specialized clinical care. To facilitate best practice in delivering healthcare for FRDA, clinical management guidelines (CMGs) were developed in 2014. However, the lack of high-certainty evidence and the inadequacy of accepted metrics to measure health status continues to present challenges in FRDA and other rare diseases. To overcome these challenges, the Grading of Recommendations Assessment and Evaluation (GRADE) framework for rare diseases developed by the RARE-Bestpractices Working Group was adopted to update the clinical guidelines for FRDA. This approach incorporates additional strategies to the GRADE framework to support the strength of recommendations, such as review of literature in similar conditions, the systematic collection of expert opinion and patient perceptions, and use of natural history data. METHODS: A panel representing international clinical experts, stakeholders and consumer groups provided oversight to guideline development within the GRADE framework. Invited expert authors generated the Patient, Intervention, Comparison, Outcome (PICO) questions to guide the literature search (2014 to June 2020). Evidence profiles in tandem with feedback from individuals living with FRDA, natural history registry data and expert clinical observations contributed to the final recommendations. Authors also developed best practice statements for clinical care points that were considered self-evident or were not amenable to the GRADE process. RESULTS: Seventy clinical experts contributed to fifteen topic-specific chapters with clinical recommendations and/or best practice statements. New topics since 2014 include emergency medicine, digital and assistive technologies and a stand-alone section on mental health. Evidence was evaluated according to GRADE criteria and 130 new recommendations and 95 best practice statements were generated. DISCUSSION AND CONCLUSION: Evidence-based CMGs are required to ensure the best clinical care for people with FRDA. Adopting the GRADE rare-disease framework enabled the development of higher quality CMGs for FRDA and allows individual topics to be updated as new evidence emerges. While the primary goal of these guidelines is better outcomes for people living with FRDA, the process of developing the guidelines may also help inform the development of clinical guidelines in other rare diseases.

Frailty score before admission as risk factor for mortality of renal patients during the first wave of the COVID pandemic in London.

Background: Frailty is a known predictor of mortality and poor outcomes during hospital admission. In this large renal retrospective cohort study, we investigated whether frailer COVID-19 positive renal patients had worse outcomes. Design: All SARS-Cov-2 positive renal patients aged ≥18 years who presented to the emergency department at the Royal Free Hospital or at the satellite dialysis centres from 10th of March until the 10th of May 2020, with recent data on frailty, were included. The follow up was until 26th of May 2020. Age, gender, ethnicity, body mass index, chronic kidney disease stage, modality of renal replacement therapy, co-morbidities, Rockwood clinical frailty score (CFS), C reactive protein and the neutrophil-to-lymphocyte count were collected at presentation. The primary outcome was the overall mortality rate following COVID-19 diagnosis. Secondary outcomes included the need for hospital admission. Results: A total of 200 renal patients were SARS-Cov-2 positive. In the 174 patients who had a CFS recorded, the age was 65.4 years ± 15.8 (mean ± SD) and 57,5% were male. At the end of follow up, 26% had died. Frail patients (CFS 5-7) were more than three times more likely to die compared to less frail patients (CFS of 1-4) (odds ratio (OR) 3.3, 95% confidence interval (CI) 1.0-10.6). 118 patients (68%) required admission, but there was no difference in hospital admission rates for frail vs non-frail patients (OR 0.6, CI 0.3-1.7). Conclusions: Frailty is a better predictor of mortality than age and co-morbidities in COVID-19 positive renal patients.

Balance Deficits due to Cerebellar Ataxia: A Machine Learning and Cloud-Based Approach.

Cerebellar ataxia (CA) refers to the disordered movement that occurs when the cerebellum is injured or affected by disease. It manifests as uncoordinated movement of the limbs, speech, and balance. This study is aimed at the formation of a simple, objective framework for the quantitative assessment of CA based on motion data. We adopted the Recurrence Quantification Analysis concept in identifying features of significance for the diagnosis. Eighty-six subjects were observed undertaking three standard neurological tests (Romberg's, Heel-shin and Truncal ataxia) to capture 213 time series inertial measurements each. The feature selection was based on engaging six different common techniques to distinguish feature subset for diagnosis and severity assessment separately. The Gaussian Naive Bayes classifier performed best in diagnosing CA with an average double cross-validation accuracy, sensitivity, and specificity of 88.24%, 85.89%, and 92.31%, respectively. Regarding severity assessment, the voting regression model exhibited a significant correlation (0.72 Pearson) with the clinical scores in the case of the Romberg's test. The Heel-shin and Truncal tests were considered for diagnosis and assessment of severity concerning subjects who were unable to stand. The underlying approach proposes a reliable, comprehensive framework for the assessment of postural stability due to cerebellar dysfunction using a single inertial measurement unit.