Early mobilisation after hip fracture surgery is associated with improved patient outcomes: A systematic review and meta-analysis.

INTRODUCTION: The aims of this systematic review and meta-analysis were to determine if after hip fracture surgery (1) early mobilisation is associated with improved clinical outcomes, and if so (2) are benefits directly proportional to how soon after surgery the patient mobilises. METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses systematic review was conducted using four databases to identify all studies that compared postoperative early mobilisation with delayed mobilisation, in patients after hip fracture surgery. The Critical Appraisal Skills Programme checklist was employed for critical appraisal and evaluation of all studies that met the inclusion criteria. RESULTS: A total of 13 studies, including 297,435 patients were identified, of which 235,275 patients were mobilised early and 62,160 were mobilised late. Six studies assessed 30-day mortality, of which two also investigated 30-day complication rates. Pooled meta-analysis demonstrated that there were significantly lower 30-day mortality rates (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.31-0.41, p < 0.001) and complication rates (OR 0.43, 95% CI 0.36-0.51, p < 0.001) in patients mobilising early after hip fracture surgery. Five studies investigated length of stay (LOS) and meta-analysis revealed no difference between groups (mean difference -0.57 days, 95% CI -1.89-0.74, p = 0.39). CONCLUSION: Early mobilisation in hip fracture patients is associated with a reduction in 30-day mortality and complication rates compared to delayed mobilisation, but no difference in LOS. These findings illustrate that early mobilisation is associated with superior post operative outcomes. However, a direct casual effect remains to be demonstrated, and further work on the factors underlying delayed mobilisation is required.

Long-term predictors of developmental outcome and disease burden in SCN1A-positive Dravet syndrome.

Dravet syndrome is a severe infantile onset developmental and epileptic encephalopathy associated with mutations in the sodium channel alpha 1 subunit gene SCN1A. Prospective data on long-term developmental and clinical outcomes are limited; this study seeks to evaluate the clinical course of Dravet syndrome over a 10-year period and identify predictors of developmental outcome. SCN1A mutation-positive Dravet syndrome patients were prospectively followed up in the UK from 2010 to 2020. Caregivers completed structured questionnaires on clinical features and disease burden; the Epilepsy & Learning Disability Quality of Life Questionnaire, the Adaptive Behavioural Assessment System-3 and the Sleep Disturbance Scale for Children. Sixty-eight of 113 caregivers (60%) returned posted questionnaires. Developmental outcome worsened at follow-up (4.45 [SD 0.65], profound cognitive impairment) compared to baseline (2.9 [SD 1.1], moderate cognitive impairment, P < 0.001), whereas epilepsy severity appeared less severe at 10-year follow-up (P = 0.042). Comorbidities were more apparent at 10-year outcome including an increase in autistic features (77% [48/62] versus 30% [17/57], χ2 = 19.9, P < 0.001), behavioural problems (81% [46/57] versus 38% [23/60], χ2 = 14.1, P < 0.001) and motor/mobility problems (80% [51/64] versus 41% [24/59], χ2 = 16.9, P < 0.001). Subgroup analysis demonstrated a more significant rise in comorbidities in younger compared to older patients. Predictors of worse long-term developmental outcome included poorer baseline language ability (P < 0.001), more severe baseline epilepsy severity (P = 0.003) and a worse SCN1A genetic score (P = 0.027). Sudden unexpected death in epilepsy had not been discussed with a medical professional in 35% (24/68) of participants. Over 90% of caregivers reported a negative impact on their own health and career opportunities. Our study identifies important predictors and potential biomarkers of developmental outcome in Dravet syndrome and emphasizes the significant caregiver burden of illness. The negative impact of epilepsy severity at baseline on long-term developmental outcomes highlights the importance of implementing early and focused therapies whilst the potential impact of newer anti-seizure medications requires further study.

Comorbidities and predictors of health-related quality of life in Dravet syndrome: A 10-year, prospective follow-up study.

OBJECTIVE: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy, leading to reduced health-related quality of life (HRQOL). Prospective outcome data on HRQOL are sparse, and this study investigated long-term predictors of HRQOL in DS. METHODS: One hundred thirteen families of SCN1A-positive patients with DS, who were recruited as part of our 2010 study were contacted at 10-year follow-up, of which 68 (60%) responded. The mortality was 5.8%. Detailed clinical and demographic information was available for each patient. HRQOL was evaluated with two epilepsy-specific instruments, the Impact of Pediatric Epilepsy Scale (IPES) and the Epilepsy & Learning Disabilities Quality of Life Questionnaire (ELDQOL); a generic HRQOL instrument, the Pediatric Quality of Life Inventory (PedsQL); and a behavioral screening tool, the Strength and Difficulties Questionnaire (SDQ). RESULTS: Twenty-eight patients were 10-15 years of age (0-5 years at baseline) and 40 were ≥16 years of age (≥6 years at baseline). Patients 0- to 5-years-old at baseline showed a significant decline in mean scores on the PedsQL total score (p = .004), physical score (p < .001), cognitive score (p = .011), social score (p = .003), and eating score (p = .030) at follow-up. On multivariate regression, lower baseline and follow-up HRQOL for the whole cohort were associated with worse epilepsy severity and a high SDQ total score (R2  = 33% and 18%, respectively). In the younger patient group, younger age at first seizure and increased severity of epilepsy were associated with a lower baseline HRQOL (R2  = 35%). In the older age group, worse epilepsy severity (F = 6.40, p = .016, R2  = 14%) and the use of sodium-channel blockers were independently associated with a lower HRQOL at 10-year follow-up (F = 4.13, p = .05, R2  = 8%). SIGNIFICANCE: This 10-year, prospective follow-up study highlights the significant HRQOL-associated cognitive, social, and physical decline particularly affecting younger patients with DS. Sodium channel blocker use appears to negatively impact long-term HRQOL, highlighting the importance of early diagnosis and disease-specific management in DS.

The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications.

Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals. Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant NaV1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants. We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4-69.3; P = 1.3 × 10-7). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current amplitude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current amplitude, consistent with stronger gain of function. Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation. Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype.

Gene variant effects across sodium channelopathies predict function and guide precision therapy.

Pathogenic variants in the voltage-gated sodium channel gene family lead to early onset epilepsies, neurodevelopmental disorders, skeletal muscle channelopathies, peripheral neuropathies and cardiac arrhythmias. Disease-associated variants have diverse functional effects ranging from complete loss-of-function to marked gain-of-function. Therapeutic strategy is likely to depend on functional effect. Experimental studies offer important insights into channel function but are resource intensive and only performed in a minority of cases. Given the evolutionarily conserved nature of the sodium channel genes, we investigated whether similarities in biophysical properties between different voltage-gated sodium channels can predict function and inform precision treatment across sodium channelopathies. We performed a systematic literature search identifying functionally assessed variants in any of the nine voltage-gated sodium channel genes until 28 April 2021. We included missense variants that had been electrophysiologically characterized in mammalian cells in whole-cell patch-clamp recordings. We performed an alignment of linear protein sequences of all sodium channel genes and correlated variants by their overall functional effect on biophysical properties. Of 951 identified records, 437 sodium channel-variants met our inclusion criteria and were reviewed for functional properties. Of these, 141 variants were epilepsy-associated (SCN1/2/3/8A), 79 had a neuromuscular phenotype (SCN4/9/10/11A), 149 were associated with a cardiac phenotype (SCN5/10A) and 68 (16%) were considered benign. We detected 38 missense variant pairs with an identical disease-associated variant in a different sodium channel gene. Thirty-five out of 38 of those pairs resulted in similar functional consequences, indicating up to 92% biophysical agreement between corresponding sodium channel variants (odds ratio = 11.3; 95% confidence interval = 2.8 to 66.9; P < 0.001). Pathogenic missense variants were clustered in specific functional domains, whereas population variants were significantly more frequent across non-conserved domains (odds ratio = 18.6; 95% confidence interval = 10.9-34.4; P < 0.001). Pore-loop regions were frequently associated with loss-of-function variants, whereas inactivation sites were associated with gain-of-function (odds ratio = 42.1, 95% confidence interval = 14.5-122.4; P < 0.001), whilst variants occurring in voltage-sensing regions comprised a range of gain- and loss-of-function effects. Our findings suggest that biophysical characterisation of variants in one SCN-gene can predict channel function across different SCN-genes where experimental data are not available. The collected data represent the first gain- versus loss-of-function topological map of SCN proteins indicating shared patterns of biophysical effects aiding variant analysis and guiding precision therapy. We integrated our findings into a free online webtool to facilitate functional sodium channel gene variant interpretation (http://SCN-viewer.broadinstitute.org).

The good and the bad: Are some attribute words better than others in the Implicit Association Test?

The Implicit Association Test (IAT) is one of the most popular measures in psychological research. A lack of standardization across IATs has resulted in significant variability among stimuli used by researchers, including the positive and negative words used in evaluative IATs. Does the variability in attribute words in evaluative IATs produce unwanted variability in measurement quality across studies? The present work investigated the effect of evaluative stimuli across three studies using 13 IATs and over 60,000 participants. The 64 positive and negative words that we tested provided similar measurement quality. Further, measurement was satisfactory even in IATs that used only category labels as stimuli. These results suggest that common sense is probably a sufficient method for selection of evaluative stimuli in the IAT. For reasonable measurement quality, we recommend that researchers using evaluative IATs in English select words randomly from the set we tested in the present research.