Abstract
Introduction
Narcolepsy type 1 (NT1) is caused by loss of hypocretins, neuropeptides that promote consolidated nocturnal sleep and sustain daytime wakefulness. In mouse models of NT1, sleep ...in the light period is characterized by more brief wake bouts, fewer long wake bouts, and longer REM sleep bouts. It is unknown if this sleep pattern is present in NT1 patients and whether it can distinguish NT1 sleep from other CNS hypersomnia conditions narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH).
Methods
Participants (6-18 years of age, drug -naïve or drug free) had diagnostic PSG/MSLT testing at Boston Children’s Hospital between 2009-2018. PSG records were rescored blinded to diagnosis. We calculated Kaplan Meier survival curves for nocturnal wake and sleep stages extracted from the nocturnal PSGs. To adjust for differences in survival related to age, sex, and race, we used Cox proportional hazards models. In total, we performed survival analysis and compared wake/sleep stages for 4 groups: NT1 (n=46), NT2 (n=12), IH (n=18) and subjective sleepy controls (n=48).
Results
NT1 patients had worse survival of wake bouts compared to controls (p<0.001). In addition, NT1 patients had decreased survival of both NREM 2 and REM sleep bouts compared to all groups (all p<0.001), and, the survival of REM sleep bouts decreased with age (p=0.006). Compared to controls, NREM 2 bouts survived longer in IH patients and whereas NREM 1 bouts survived longer in the NT2 group (p’s<0.006). There were no group effects for NREM 3, but survival of NREM 3 was less in the older IH patients compared to older controls (p<0.02).
Conclusion
Pediatric NT1 patients have unique sleep fragmentation characterized by unstable wake, NREM 2 and REM bouts. Though less severe as NT1, NT2 patients sustain lighter sleep. In contrast, IH patients show overly stable NREM stage 2 sleep and plausibly this contributes to their characteristic sleep inertia. Further research is needed to determine if sleep stability patterns can be used to diagnose CNS hypersomnia conditions and differentiate treatment responsiveness.
Support
K23 National Institutes of Health (NINDS, K23 NS104267-01A1) and Investigator Initiated Research grants from Jazz Pharmaceuticals, Inc. (Dr. Maski)
Category:
Ankle; Basic Sciences/Biologics
Introduction/Purpose:
Extracorporeal shockwave therapy (ESWT) is a non-invasive treatment modality that is utilized in the treatment of chronic Achilles ...tendinopathy (AT).
The purpose of this study was to retrospectively assess outcomes following ESWT for both NAT and IAT at greater than 1-year follow-up, and to identify potential predictors of outcomes.
Methods:
Chart review was conducted to identify patients who underwent ESWT for AT with a minimum of 1-year follow-up. Data collected and assessed included: patient demographics, pathological characteristics, treatment characteristics, Victorian Institute of Sports Assessment-Achilles (VISA-A) and visual analog scale (VAS) scores and failures. Linear regression was performed to identify potential predictors of outcomes. Survival analysis was conducted using Kaplan Meier curves.
Fifty-two cases of IAT and 34 cases of NAT were included. The mean follow-up in the NAT cohort was 22.3±10.2 months and the mean follow-up time in the IAT cohort was 26.8±15.8 months.
Results:
Improvements in VISA-A and VAS scores were observed in the NAT cohort at 6 months follow-up and at final follow-up (p < 0.01). Improvements in VISA-A scores and VAS scores were recorded in the IAT cohort at 6 months follow-up which subsequently deteriorated at final follow-up. In the NAT cohort, the failure rate at 6 months follow-up was 11.8% which increased to 29.4% at final follow-up. In the IAT cohort, the failure rate at 6 months follow-up was 32.7% which increased to 59.6% at final follow-up. Predictors of poor outcomes in the NAT cohort included pre-ESWT subjective clinical score, male, presence of cardiovascular risk factor, and increasing MRI severity. Predictors of poor outcomes in the IAT cohort included pre-ESWT subjective clinical score and increasing MRI severity.
Conclusion:
This study found that superior subjective clinical outcomes together with a lower failure rate maintained over 1 year in the NAT cohort compared to the IAT cohort. This may implicate ESWT as a temporising treatment in IAT and a longer term solution in patients with NAT.
Efforts to identify important risk factors for cognitive impairment and dementia have to date mostly relied on meta-analytic strategies. A comprehensive empirical evaluation of these risk factors ...within a single study is currently lacking.
We used a combined methodology of machine learning and semi-parametric survival analysis to estimate the relative importance of 52 predictors in forecasting cognitive impairment and dementia in a large, population-representative sample of older adults.
Participants from the Health and Retirement Study (N = 9,979; aged 50-98 years) were followed for up to 10 years (M = 6.85 for cognitive impairment; M = 7.67 for dementia). Using a split-sample methodology, we first estimated the relative importance of predictors using machine learning (random forest survival analysis), and we then used semi-parametric survival analysis (Cox proportional hazards) to estimate effect sizes for the most important variables.
African Americans and individuals who scored high on emotional distress were at relatively highest risk for developing cognitive impairment and dementia. Sociodemographic (lower education, Hispanic ethnicity) and health variables (worse subjective health, increasing BMI) were comparatively strong predictors for cognitive impairment. Cardiovascular factors (e.g., smoking, physical inactivity) and polygenic scores (with and without APOEɛ4) appeared less important than expected. Post-hoc sensitivity analyses underscored the robustness of these results.
Higher-order factors (e.g., emotional distress, subjective health), which reflect complex interactions between various aspects of an individual, were more important than narrowly defined factors (e.g., clinical and behavioral indicators) when evaluated concurrently to predict cognitive impairment and dementia.
BackgroundReal-world, long-term adherence and effectiveness data is vital to complement our under- standing of therapies, which is often based on short-term clinical trials. Here we explored disease ...modifying therapy (DMT) durability in a UK-wide cohort of people with Multiple Sclerosis (pwMS).MethodsIn this cohort study, which included 4,415 pwMS from 10 UK MS centres, 6,960 DMT prescrip- tions were included in the analysis (mean 1.7, range 1-6 per patient). Prescriptions without accurate start dates were excluded (n=90). Kaplan-Meier survival analysis was used to model DMT persistence (days from prescription start to stop), which was used to calculate 2, 5 and 10-year durability (% of prescrip- tions continuing).ResultsTwo-year durability was highest for immune reconstitution therapies cladribine (98%), ocrelizumab (96%), and alemtuzumab (95%). Oral therapies fingolimod (74%) and dimethyl fumarate (73%), and intravenous natalizumab (78%) shared similar durability. Injectable therapies glatiramer acetate (51%) and interferon (55%), had lowest durability. Potential confounding factors include variable date of DMT licensing, change in DMT algorithms over time and increasing DMT options.ConclusionThis multi-centre study has revealed highly variable durability between DMTs over time, which may impact real-world effectiveness. These results may inform DMT clinical decision-making and improve outcomes for pwMS.
IntroductionLiverpool is an area of high socioeconomic deprivation, with more than twice the national incidence of lung cancer. In order to benchmark our survival performance at the Liverpool Lung ...Cancer Unit (diagnosing about 400 new cases/year) we wanted to compare our Units performance against national figures (32% 1 year survival, and 10% 5 year survival). We were also interested in determining if our survival rates had changed over time.MethodsWe conducted a retrospective analysis of data for all patients diagnosed over a period of 9 years. All analyses were conducted on the entire dataset stratified on the basis of 3 years’ time intervals (2007–2009; 2010–2012; 2013–2015). Demographic data were analysed and compared using descriptive statistics. Survival analysis was conducted by Kaplan Meier survival plots and log- Rank tests. P-values less than 5% were considered statistically significant.Results3710 patients were diagnosed, with a mean age of 71.3, 52.5% male. Performance state (PS) 0=15%, 1=29.4%, 2=22.2%, 3=19.8%, 4=6.4%. Stage at diagnosis 1=19.7%, 2=6.6%, 3=23.3%, 4=41.3%. There was no significant change in numbers, age, PS, histological subtypes and stage over the 3 time periods. However, a survival rate of 40% and 16% was observed for 1 year and 5 years respectively, which is higher than the national average (figure 1). In addition, there was an increase in survival for patients diagnosed in latter time period compared with the earlier time periods. Interestingly, only stage IV patients showed significant improvement in survival for 2013–2015(p<0.001), a pattern that strongly correlated with an increased oncological treatments (both chemotherapy and radiotherapy) 41.7% vs 57.0% (p<0.001). The differences in survival for stage IV patients did not relate with any significant change in age, gender, histological subtype or PS.ConclusionsSurvival rates for our unit are higher than the national average. An increase in oncological treatments for stage IV patients appears to have contributed to the significant improvement in survival for these patients.Abstract P260 Figure 1
IntroductionAnimal models and human post-mortem analysis show activation of the unfolded protein response (UPR) in motor neuron disease (MND). The role the UPR plays in MND caused by mutations in ...C9ORF72 and TARDBP is poorly understood and it may be detrimental to neuronal survival.AimDetermine whether induced pluripotent stem cell (iPSC)-derived spinal motor neurons from patients with mutations in C9ORF72 and TARDBP show UPR activation by three weeks post platedown.MethodsIPSCs from control and MND patients with mutation-corrected isogenic pairs were converted into spinal motor neurons using the Nedelec protocol. Survival analysis with calcein AM was determined by baseline imaging and at 24 and 48 hour timepoints for C9ORF72 and TARDBP mutants. PERK, IRE1 and ATF6, markers of endoplasmic reticulum stress, were assessed by Western blotting. XBP activation was probed by qPCR and splicing assays.Preliminary and ResultsThe project is ongoing but at the time of submission survival in response to tunicamycin doses between 1 µg/mL and 50 µg/mL does not vary significantly between C9ORF72 mutants and their isogenic controls. The TARDBP tunicamycin survival assay is ongoing. ATF6 was significantly upregulated in TARDBP mutants at three weeks but normal in C9ORF72 mutant cells.
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