The immune cell transcriptome is modulated by vitamin D3 supplementation in people with a first demyelinating event participating in a randomized placebo-controlled trial.

Vitamin D deficiency is a risk factor for developing multiple sclerosis. The PrevANZ trial was conducted to determine if vitamin D3 supplementation can prevent recurrent disease activity in people with a first demyelinating event. As a sub-study of this trial, we investigated the effect of supplementation on peripheral immune cell gene expression. Participants were randomized to 1000, 5000 or 10,000 international units daily of vitamin D3 or placebo. Peripheral blood was collected at baseline and 12 weeks and sent for ribonucleic acid sequencing. Datasets from 55 participants were included. Gene expression was modulated by high dose supplementation. Antigen presentation and viral response pathways were upregulated. Oxidative phosphorylation and immune signaling pathways, including tumor necrosis factor-alpha and interleukin-17 signaling, were downregulated. Overall, vitamin D3 supplementation for 12 weeks modulated the peripheral immune cell transcriptome with induction of anti-inflammatory gene expression profiles. Our results support a dose-dependent effect of vitamin D3 supplementation on immune gene expression.

Toward designing human intervention studies to prevent osteoarthritis after knee injury: A report from an interdisciplinary OARSI 2023 workshop.

Objective: The global impact of osteoarthritis is growing. Currently no disease modifying osteoarthritis drugs/therapies exist, increasing the need for preventative strategies. Knee injuries have a high prevalence, distinct onset, and strong independent association with post-traumatic osteoarthritis (PTOA). Numerous groups are embarking upon research that will culminate in clinical trials to assess the effect of interventions to prevent knee PTOA despite challenges and lack of consensus about trial design in this population. Our objectives were to improve awareness of knee PTOA prevention trial design and discuss state-of-the art methods to address the unique opportunities and challenges of these studies. Design: An international interdisciplinary group developed a workshop, hosted at the 2023 Osteoarthritis Research Society International Congress. Here we summarize the workshop content and outputs, with the goal of moving the field of PTOA prevention trial design forward. Results: Workshop highlights included discussions about target population (considering risk, homogeneity, and possibility of modifying osteoarthritis outcome); target treatment (considering delivery, timing, feasibility and effectiveness); comparators (usual care, placebo), and primary symptomatic outcomes considering surrogates and the importance of knee function and symptoms other than pain to this population. Conclusions: Opportunities to test multimodal PTOA prevention interventions across preclinical models and clinical trials exist. As improving symptomatic outcomes aligns with patient and regulator priorities, co-primary symptomatic (single or aggregate/multidimensional outcome considering function and symptoms beyond pain) and structural/physiological outcomes may be appropriate for these trials. To ensure PTOA prevention trials are relevant and acceptable to all stakeholders, future research should address critical knowledge gaps and challenges.

Utilising electrodermal activity sensor signals to quantify nociceptive response during movement activities.

OBJECTIVE: With an increasingly ageing population and osteoarthritis prevalence, the quantification of nociceptive signals responsible for painful movements and individual responses could lead to better treatment and monitoring solutions. Changes in electrodermal activity (EDA) can be detected via changes in skin conductance (SC) and measured using finger electrodes on a wearable sensor, providing objective information for increased physiological stress response. RESULTS: To provide EDA response preliminary data, this was recorded with healthy volunteers on an array of activities while receiving a noxious stimulus. This provides a defined scenario that can be utilised as protocol feasibility testing. Raw signal extraction, processing and statistical analysis was performed using mean SC values on all participant data. The application of the stimuli resulted in a significant average increase (p < 0.05) in mean SC in four out of five activities with significant gender differences (p < 0.05) in SC and self-reported pain scores and large effect sizes. Though EDA parameters are a promising tool for nociceptive response indicators, limitations including motion artifact sensitivities and lack of previous movement-based EDA published data result in restricted analysis understanding. Refined processing pipelines with signal decomposition tools could be utilised in a protocol that quantifies nociceptive response clinically meaningfully.

Vitamin D did not reduce multiple sclerosis disease activity after a clinically isolated syndrome.

Low serum levels of 25-hydroxyvitamin D (25(OH)D), and low sunlight exposure, are known risk factors for the development of multiple sclerosis. Add-on vitamin D supplementation trials in established multiple sclerosis have been inconclusive. The effects of vitamin D supplementation to prevent multiple sclerosis is unknown. We aimed to test the hypothesis that oral vitamin D3 supplementation in high-risk clinically isolated syndrome (abnormal MRI, at least three T2 brain and/or spinal cord lesions), delays time to conversion to definite multiple sclerosis, that the therapeutic effect is dose-dependent, and that all doses are safe and well tolerated. We conducted a double-blind trial in Australia and New Zealand. Eligible participants were randomised 1:1:1:1 to placebo, 1000, 5000, or 10 000 IU of oral vitamin D3 daily within each study centre (n=23) and followed for up to 48 weeks. Between 2013 and 2021, we enrolled 204 participants. Brain MRI scans were performed at baseline, 24 and 48 weeks. The main study outcome was conversion to clinically definite multiple sclerosis based on the 2010 McDonald criteria defined as either a clinical relapse or new brain MRI T2 lesion development. We included 199 cases in the intention-to-treat analysis based on assigned dose. Of these, 116 converted to multiple sclerosis by 48 weeks (58%). Compared to placebo, the HRs (95%CI) for conversion were 1000 IU 0.87 (0.50, 1.50); 5000 IU 1.37 (0.82, 2.29); and 10 000 IU 1.28 (0.76, 2.14). In an adjusted model including age, sex, latitude, study centre, and baseline symptom number, clinically isolated syndrome onset site, presence of infratentorial lesions, and use of steroids, the HRs (versus placebo) were 1000 IU 0.80 (0.45, 1.44); 5000 IU 1.36 (0.78, 2.38); 10 000 IU 1.07 (0.62, 1.85). Vitamin D3 supplementation was safe and well tolerated. We did not demonstrate reduction in multiple sclerosis disease activity by vitamin D3 supplementation after a high-risk clinically isolated syndrome. Trial registration Australian Clinical Trials Registration Number ACTRN12612001160820.

Multiple sclerosis mortality in New Zealand: a nationwide prospective study.

BACKGROUND: Mortality data from Europe and North America show a shorter life expectancy for people with multiple sclerosis (MS). It is not known if a similar mortality risk exists in the southern hemisphere. We analysed the mortality outcomes of a comprehensive New Zealand (NZ) MS cohort, 15 years postrecruitment. METHODS: All participants of the nationwide 2006 NZ MS prevalence study were included and mortality outcomes were compared with life table data from the NZ population using classic survival analyses, standardised mortality ratios (SMRs) and excess death rates (EDRs). RESULTS: Of 2909 MS participants, 844 (29%) were deceased at the end of the 15-year study period. Median survival age for the MS cohort was 79.4 years (78.5, 80.3), compared with 86.6 years (85.5, 87.7) for the age-matched and sex-matched NZ population. The overall SMR was 1.9 (1.8, 2.1)). Symptom onset between 21 and 30 years corresponded to an SMR of 2.8 and a median survival age 9.8 years lower than the NZ population. Progressive-onset disease was associated with a survival gap of 9 years compared with 5.7 years for relapsing onset. The EDR for those diagnosed in 1997-2006 was 3.2 (2.6, 3.9) compared with 7.8 (5.8, 10.3) for those diagnosed between 1967 and 1976. CONCLUSIONS: New Zealanders with MS have a median survival age 7.2 years lower than the general population and twice the mortality risk. The survival gap was greater for progressive-onset disease and for those with an early age of onset.

Using the EQ-5D-5L to investigate quality-of-life impacts of disease-modifying therapy policies for people with multiple sclerosis (MS) in New Zealand.

BACKGROUND: Health state utilities (HSU) are a health-related quality-of-life (HRQoL) input for cost-utility analyses used for resource allocation decisions, including medication reimbursement. New Zealand (NZ) guidelines recommend the EQ-5D instruments; however, the EQ-5D-5L may not sufficiently capture psychosocial health. We evaluated HRQoL among people with multiple sclerosis (MS) in NZ using the EQ-5D-5L and assessed the instrument's discriminatory sensitivity for a NZ MS cohort. METHODS: Participants were recruited from the NZ MS Prevalence Study. Participants self-completed a 45-min online survey that included the EQ-5D-5L/EQ-VAS. Disability severity was classified using the Expanded Disability Status Scale (EDSS) to categorise participant disability as mild (EDSS: 0-3.5), moderate (EDSS: 4.0-6.0) and severe (EDSS: 6.5-9.5). Anxiety/depression were also measured using the Hospital Anxiety and Depression Score (HADS). In the absence of an EQ-5D-5L NZ tariff, HSUs were derived using an Australian tariff. We evaluated associations between HSUs and participant characteristics with linear regression models. RESULTS: 254 participants entered the study. Mean age was 55.2 years, 79.5% were female. Mean (SD) EQ-5D-5L HSU was 0.58 (0.33). Mean (SD) HSUs for disability categories were: mild 0.80 ± 0.17, moderate 0.57 ± 0.21 and severe 0.14 ± 0.32. Twelve percent reported HSU = 1.0 (i.e., no problems in any domain). Participants who had never used a disease-modifying therapy reported a lower mean HSU. Multivariable modelling found that the HADS anxiety score was not associated with EQ-5D-5L. CONCLUSIONS: HRQoL for people with MS in NZ was lower than comparable countries, including Australia. We suggest a comparison with other generic tools that may have improved sensitivity to mental health.

Research priorities to reduce the impact of musculoskeletal disorders: a priority setting exercise with the child health and nutrition research initiative method.

Involving research users in setting priorities for research is essential to ensure the outcomes are patient-centred and maximise its value and impact. The Musculoskeletal Disorders Research Advisory Group Versus Arthritis led a research priority setting exercise across musculoskeletal disorders. The Child Health and Nutrition Research Initiative (CHNRI) method of setting research priorities with a range of stakeholders was used, involving four stages and two surveys, to: (1) gather research uncertainties, (2) consolidate these, (3) score uncertainties against importance and impact, and (4) analyse scoring for prioritisation. 213 people responded to the first survey and 285 people to the second, representing clinicians, researchers, and people with musculoskeletal disorders. Key priorities included developing and testing new treatments, better treatment targeting, early diagnosis, prevention, and better understanding and management of pain, with an emphasis on understanding underpinning mechanisms. We present a call to action to researchers and funders to target these priorities.

Response to treatment in NMOSD: the Australasian experience.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is associated with significant morbidity and mortality. Several therapies have been recommended for NMOSD and more recently clinical trials have demonstrated efficacy for three monoclonal antibody therapies. We present a retrospective observational study of treatment response in NMOSD. METHODS: This was a retrospective, unblinded, observational study of treatment efficacy for rituximab and traditional immunosuppressive therapy in patients with AQP4 antibody positive NMOSD. Treatment efficacy was assessed using annualised relapse rates (ARR), time to first relapse and expanded disability status scale (EDSS) scores. RESULTS: Complete relapse and treatment data were available for 43/68 (63%) of AQP4 antibody positive NMOSD cases covering 74 episodes of treatment. In a time to first relapse analysis rituximab showed a risk ratio of 0.23 (95% CI 0.08 - 0.65) when compared with no treatment and there was a non-significant reduction in ARR of 35% compared to pre-treatment. ß-interferon (p = 0.0002) and cyclophosphamide (p = 0.0034) were associated with an increased ARR compared to pre-treatment. Rituximab (median 4.0 [range 0.0 - 7.0]; p = 0.042) and traditional immunosuppressive therapy (median 4.0 [range 0.0 - 8.0]; p = 0.016) were associated with a lower final EDSS compared to ß-interferon (median 6.0 [range 4.0 - 7.5]). CONCLUSIONS: These data provide additional support for the use of rituximab in preference to traditional immunosuppressive agents and MS disease modifying therapies as first line treatment of NMOSD.

Standardized mortality ratios in multiple sclerosis: Systematic review with meta-analysis.

OBJECTIVE: To perform a meta-analysis of all-cause, cause-specific and gender-specific standardized mortality ratio and crude mortality rate for people with multiple sclerosis. We also examined the temporal trends in this data. METHODS: Medline, Cochrane Library and Scopus were searched. Keywords were "multiple sclerosis" and "standardized mortality ratio" or "Standardized Mortality Ratio". We included longitudinal studies with available data on the number of deaths, follow-up period, person years and reports of standardized mortality ratio (SMR). Crude mortality ratio (CMR) was calculated and SMR was extracted. CMRs and log-SMR were pooled by the method of inverse variance. Meta-regression models were used to investigate temporal trends. RESULTS: Fifty-seven articles were screened. Fifteen studies were included covering a period 1949-2013 (160,000 patients; 21,225 deaths). The all-cause SMR for people with MS was 2.61 (95% CI 2.58 to 2.65). For men this was 2.47 (95% CI 2.42 to 2.52) and for women 2.57 (95% CI 2.53 to 2.61). The CMR was 13.45/1000 person years. Cause-specific SMR was 1.74 (1.67 to 1.81) for CVD, 4.70 (4.45 to 4.87) for respiratory disease and infection, 1.81 (1.64 to 2.0) for accident and suicide and 0.99 (0.93 to 1.06) for cancer. Meta-regression analysis of the SMR compared to midpoint follow-up year revealed no relationship (co-efficient 0.001, p = .98). CONCLUSIONS: People with multiple sclerosis (MS) have reduced overall survival and increased risk of death from cardiovascular, respiratory and infectious disease as well as accidents and suicide. This does not appear to have changed over the last 65 years.

NMOSD and MS prevalence in the Indigenous populations of Australia and New Zealand.

BACKGROUND: We studied the prevalence of neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) in Indigenous populations of Australia and New Zealand with the aim of assessing potential differences. METHODS: Cases of possible NMOSD and MS were collected from Australia and New Zealand. Clinical details, MR imaging, and serologic results were used to apply 2015 IPND diagnostic criteria for NMOSD and 2010 McDonald criteria for MS. Frequencies of self-determined ethnic ancestry were calculated for confirmed NMOSD, suspected NMOSD, and MS. Prevalence rates for NMOSD and MS according to ancestry were compared. RESULTS: There were 75 cases with NMOSD, 89 with suspected NMSOD, and 101 with MS. NMOSD cases were more likely to have Asian, Indigenous, or Other ancestry compared to suspected NMOSD or MS. There were no differences in the clinical phenotype of NMOSD seen in Indigenous compared to European ancestry populations. Per 100,000, the prevalence estimate for NMOSD in people with Maori ancestry was 1.50 (95% CI 0.52-2.49) which was similar to those with Asian ancestry 1.57 (95% CI 1.15-1.98). NMOSD prevalence in Australian Aboriginal and Torres Strait Islander populations was 0.38 (95% CI 0.00-0.80) per 100,000. CONCLUSION: The prevalence of NMOSD in the Maori population is similar to South East Asian countries, reflecting their historical origins. The prevalence of MS in this group is intermediate between those with South East Asian and European ancestry living in New Zealand. Both NMOSD and particularly MS appear to be uncommon in the Indigenous populations of Australia.

The effect of national disease-modifying therapy subsidy policy on long-term disability outcomes in people with multiple sclerosis.

BACKGROUND: Disease-modifying therapies (DMTs) are used to treat people with relapsing-onset multiple sclerosis (ROMS), but our knowledge is largely limited to their short-term effects. OBJECTIVE: To determine (1) the impact of national-level DMT subsidy policy on DMT use and health outcomes in people with MS (PwMS) and (2) the long-term effects of DMT on disability and quality of life (QoL; 5-level EQ-5D version (EQ-5D-5L) utility value). METHODS: This observational cohort study compared Australian and New Zealand populations with different levels of DMT availability 10-20 years post-ROMS diagnosis. Between-country differences were assessed using standardised differences. Associations were assessed with multivariable linear regression models. RESULTS: We recruited 328 Australians and 256 New Zealanders. The Australian cohort had longer DMT treatment duration, greater proportion of disease course treated and shorter duration between diagnosis and starting DMT. The Australian cohort had lower median Expanded Disability Status Scale (EDSS) (3.5 vs 4.0) and Multiple Sclerosis Severity Score (MSSS) (3.05 vs 3.71) and higher QoL (0.71 vs 0.65). In multivariable models, between-country differences in disability and QoL were largely attributed to differential use of DMT. CONCLUSIONS: This study provides evidence for the impact of national-level DMT policy on disability outcomes in PwMS. Where DMTs are more accessible, PwMS experienced less disability progression and improved QoL 10-20 years post-diagnosis.

MRI Patterns Distinguish AQP4 Antibody Positive Neuromyelitis Optica Spectrum Disorder From Multiple Sclerosis.

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the CNS. Overlap in the clinical and MRI features of NMOSD and MS means that distinguishing these conditions can be difficult. With the aim of evaluating the diagnostic utility of MRI features in distinguishing NMOSD from MS, we have conducted a cross-sectional analysis of imaging data and developed predictive models to distinguish the two conditions. NMOSD and MS MRI lesions were identified and defined through a literature search. Aquaporin-4 (AQP4) antibody positive NMOSD cases and age- and sex-matched MS cases were collected. MRI of orbits, brain and spine were reported by at least two blinded reviewers. MRI brain or spine was available for 166/168 (99%) of cases. Longitudinally extensive (OR = 203), "bright spotty" (OR = 93.8), whole (axial; OR = 57.8) or gadolinium (Gd) enhancing (OR = 28.6) spinal cord lesions, bilateral (OR = 31.3) or Gd-enhancing (OR = 15.4) optic nerve lesions, and nucleus tractus solitarius (OR = 19.2), periaqueductal (OR = 16.8) or hypothalamic (OR = 7.2) brain lesions were associated with NMOSD. Ovoid (OR = 0.029), Dawson's fingers (OR = 0.031), pyramidal corpus callosum (OR = 0.058), periventricular (OR = 0.136), temporal lobe (OR = 0.137) and T1 black holes (OR = 0.154) brain lesions were associated with MS. A score-based algorithm and a decision tree determined by machine learning accurately predicted more than 85% of both diagnoses using first available imaging alone. We have confirmed NMOSD and MS specific MRI features and combined these in predictive models that can accurately identify more than 85% of cases as either AQP4 seropositive NMOSD or MS.

A Multi-Step Model of Parkinson's Disease Pathogenesis.

BACKGROUND: Parkinson's disease (PD) may result from the combined effect of multiple etiological factors. The relationship between disease incidence and age, as demonstrated in the cancer literature, can be used to model a multistep pathogenic process, potentially affording unique insights into disease development. OBJECTIVES: We tested whether the observed incidence of PD is consistent with a multistep process, estimated the number of steps required and whether this varies with age, and examined drivers of sex differences in PD incidence. METHODS: Our validated probabilistic modeling process, based on medication prescribing, generated nationwide age- and sex-adjusted PD incidence data spanning 2006-2017. Models of log(incidence) versus log(age) were compared using Bayes factors, to estimate (1) if a linear relationship was present (indicative of a multistep process); (2) the relationship's slope (one less than number of steps); (3) whether slope was lower at younger ages; and (4) whether slope or y-intercept varied with sex. RESULTS: Across >15,000 incident cases of PD, there was a clear linear relationship between log(age) and log(incidence). Evidence was strongest for a model with an initial slope of 5.2 [3.8, 6.4], an inflexion point at age 45, and beyond this a slope of 6.8 [6.4, 7.2]. There was evidence for the intercept varying by sex, but no evidence for slope being sex-dependent. CONCLUSIONS: The age-specific incidence of PD is consistent with a process that develops in multiple, discrete steps - on average six before age 45 and eight after. The model supports theories emphasizing the primacy of environmental factors in driving sex differences in PD incidence. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The latitude gradient for multiple sclerosis prevalence is established in the early life course.

The strongest epidemiological clue that the environment at the population level has a significant impact on the risk of developing multiple sclerosis is the well established, and in many instances, increasing latitudinal gradient of prevalence, incidence and mortality globally, with prevalence increasing by up to 10-fold between the equator and 60° north and south. The drivers of this gradient are thought to be environmental with latitude seen as a proxy for ultraviolet radiation and thus vitamin D production; however, other factors may also play a role. Several important questions remain unanswered, particularly when in the life course is the gradient established, does lifetime migration mitigate or exacerbate previously reported latitude gradients at location of diagnosis, and do factors such as sex or multiple sclerosis disease phenotype influence the timing or significance of the gradient? Utilizing lifetime residence calendars collected as part of the New Zealand National Multiple Sclerosis Prevalence Study, we constructed lifetime latitudinal gradients for multiple sclerosis from birth to prevalence day in 2006 taking into account migration internally and externally and then analysed by sex and multiple sclerosis clinical course phenotype. Of 2917 individuals living in New Zealand on prevalence day, 7 March 2006, with multiple sclerosis, 2127 completed the life course questionnaire and of these, 1587 were born in New Zealand. All cohorts and sub-cohorts were representative of the overall multiple sclerosis population in New Zealand on prevalence day. We found that the prevalence gradient was present at birth and was, in fact, stronger than at census day, and the slope of the gradient persisted until the age of 12 before gradually declining. We found that internal and external migration into New Zealand had little, if any, effect on the gradient except to decrease the significance of the gradient somewhat. Finally, we found as we had reported previously, that the lifetime prevalence gradients were largely driven by females with relapse onset multiple sclerosis. These findings confirm for the first time the importance of early life environmental exposures in the risk of multiple sclerosis indicating strongly that exposures as early as in utero and at birth drive the latitudinal gradient. Consequently, prevention studies should be focused on high-risk individuals and populations from the earliest possible time points especially, when appropriate, on females.

Routine Use of Tenecteplase for Thrombolysis in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: In ischemic stroke, intravenous tenecteplase is noninferior to alteplase in selected patients and has some practical advantages. Several stroke centers in New Zealand changed to routine off-label intravenous tenecteplase due to improved early recanalization in large vessel occlusion, inconsistent access to thrombectomy within stroke networks, and for consistency in treatment protocols between patients with and without large vessel occlusion. We report the feasibility and safety outcomes in tenecteplase-treated patients. METHODS: We performed a retrospective analysis of consecutive patients thrombolyzed with intravenous tenecteplase at 1 comprehensive and 2 regional stroke centers from July 14, 2018, to February 29, 2020. We report the baseline clinical characteristics, rates of symptomatic intracranial hemorrhage, and angioedema. These were then compared with patient outcomes with those treated with intravenous alteplase at 2 other comprehensive stroke centers. Multivariable mixed-effects logistic regression models were performed assessing the association of tenecteplase with symptomatic intracranial hemorrhage and independent outcome (modified Rankin Scale score, 0-2) at day 90. RESULTS: There were 165 patients treated with tenecteplase and 254 with alteplase. Age (75 versus 74 years), sex (56% versus 60% male), National Institutes of Health Stroke Scale scores (8 versus 10), median door-to-needle times (47 versus 48 minutes), or onset-to-needle time (129 versus 130 minutes) were similar between the groups. Symptomatic intracranial hemorrhage occurred in 3 (1.8% [95% CI, 0.4-5.3]) tenecteplase patients compared with 7 (2.7% [95% CI, 1.1-5.7]) alteplase patients (P=0.75). There were no differences between tenecteplase and alteplase in the rates of angioedema (4 [2.4%; 95% CI, 0.7-6.2] versus 1 [0.4%; 95% CI, 0.01-2.2], P=0.08) or 90-day functional independence (100 [61%] versus 140 [57%], P=0.47), respectively. In mixed-effects logistic regression models, there was no significant association between thrombolytic choice and symptomatic intracranial hemorrhage (odds ratio tenecteplase, 0.62 [95% CI, 0.14-2.80], P=0.53) or functional independence (odds ratio tenecteplase, 1.20 [95% CI, 0.74-1.95], P=0.46). CONCLUSIONS: Routine use of tenecteplase for stroke thrombolysis was feasible and had comparable safety profile and outcome to alteplase.

Prevention of posttraumatic osteoarthritis at the time of injury: Where are we now, and where are we going?

This overview of progress made in preventing post-traumatic osteoarthritis (PTOA) was delivered in a workshop at the Orthopaedics Research Society Annual Conference in 2019. As joint trauma is a major risk factor for OA, defining the molecular changes within the joint at the time of injury may enable the targeting of biological processes to prevent later disease. Animal models have been used to test therapeutic targets to prevent PTOA. A review of drug treatments for PTOA in rodents and rabbits between 2016 and 2018 revealed 11 systemic interventions, 5 repeated intra-articular or topical interventions, and 5 short-term intra-articular interventions, which reduced total Osteoarthritis Research Society International scores by 30%-50%, 20%-70%, and 0%-40%, respectively. Standardized study design, reporting of effect size, and quality metrics, alongside a "whole joint" approach to assessing efficacy, would improve the translation of promising new drugs. A roadblock to translating preclinical discoveries has been the lack of guidelines on the design and conduct of human trials to prevent PTOA. An international workshop addressing this in 2016 considered inclusion criteria and study design, and advocated the use of experimental medicine studies to triage candidate treatments and the development of early biological and imaging biomarkers. Human trials for the prevention of PTOA have tested anakinra after anterior cruciate ligament rupture and dexamethasone after radiocarpal injury. PTOA offers a unique opportunity for defining early mechanisms of OA to target therapeutically. Progress in trial design and high-quality preclinical research, and allegiance with patients, regulatory bodies, and the pharmaceutical industry, will advance this field.

Functional neurological disorders presenting as emergencies to secondary care.

BACKGROUND: Functional neurological disorders (FND) represent a significant proportion of presentations to outpatient adult neurology services. There is little information relating to patients presenting to acute inpatient care. METHODS: We identified patients presenting as acute admissions with FND to Christchurch Hospital, Christchurch, New Zealand, from 2016 to 2018. We analyzed relevant demographic and clinical data from electronic records and measured incidence of presentation to secondary care and healthcare utilization. RESULTS: One hundred sixty-two patients presented on 173 occasions with FND, representing 9% of all admissions to the neurology service during the 3-year study period. The mean age was 40 (SD 17) years, 111 (69%) patients were female and the median length of stay was 3 (IQR 2-4) days. A total of 92 computed tomography brain scans, 77 magnetic resonance imaging brain scans and 42 electroencephalograms were carried out. On 22 (13%) occasions, patients were referred for outpatient psychological therapy. In the 3 years prior to each patient's last presentation in the study period, these 162 patients had a total of 671 presentations to the emergency department. Healthcare demand did not decrease after the index admission. The rate of acute inpatient admission for FND was 10 per 100,000 per year for the total Christchurch Hospital catchment, 6/100,000/year in rural areas, and 11/100,000/year in urban areas. CONCLUSION: FND represented almost 1 in 10 acute neurology admissions with significant inpatient healthcare resource utilization.

The neuro-otology of Susac syndrome.

OBJECTIVE: We characterised the clinical and neuro-otological characteristics of patients with Susac syndrome. METHODS: The medical records of 30 patients with Susac syndrome were reviewed for details of their clinical presentation and course, neuro-otological symptoms, investigation results including audiology and vestibular function tests, treatment and outcomes. RESULTS: Our findings demonstrate that 29 of our 30 patients with Susac syndrome developed neuro-otological symptoms such as hearing loss, disequilibrium, tinnitus or vertigo during their disease course. Hearing loss was the most common neuro-otological symptom occurring in 93% of patients. A rising configuration of low-frequency greater than the high-frequency sensorineural hearing loss was the most characteristic finding on audiological testing (37% of reviewed audiograms). Disproportionately poor speech discrimination was identified in 20% of cases, and one case demonstrated a retrocochlear pattern on electrophysiological testing. Four patients required hearing aids and a further two patients required a cochlear implant due to severe hearing loss. Two out of two treated patients had improvements in hearing after the prompt administration of corticosteroids, indicating the potential for recoverable hearing loss if relapses are treated early. Effects on vestibular function were variable in ten patients who were tested, with most showing preservation of function despite significant hearing loss. CONCLUSIONS: Neuro-otological symptoms in Susac syndrome are almost universal. In the correct clinical context, a rising configuration of low to high-frequency sensorineural hearing loss should prompt consideration of Susac syndrome. Treatment of inner ear symptoms in Susac syndrome requires further research as early immunotherapy may be beneficial.