What are the Differences in Injury Proportions Between Different Populations of Runners?:A Systematic Review and Meta-Analysis

_Background:_ Many runners suffer from injuries. No information on high-risk populations is available so far though. _Objectives:_ The aims of this study were to systematically review injury proportions in different populations of runners and to compare injury locations between these populations. _Data Sources:_ An electronic search with no date restrictions was conducted up to February 2014 in the PubMed, Embase, SPORTDiscus and Web of Science databases. The search was limited to original articles written in English. The reference lists of the included articles were checked for potentially relevant studies. _Study Eligibility Criteria:_ Studies were eligible when the proportion of running injuries was reported and the participants belonged to one or more homogeneous populations of runners that were clearly described. Study selection was conducted by two independent reviewers, and disagreements were resolved in a consensus meeting. _Study Appraisal and Synthesis Methods:_ Details of the study design, population of runners, sample size, injury definition, method of injury assessment, number of injuries and injury locations were extracted from the articles. The risk of bias was assessed with a scale consisting of eight items, which was specifically developed for studies focusing on musculoskeletal complaints. _Results:_ A total of 86 articles were included in this review. Where possible, injury proportions were pooled for each identified population of runners, using a random-effects model. Injury proportions were affected by injury definitions and durations of follow-up. Large differences between populations existed. The number of medical-attention injuries during an event was small for most populations of runners, except for ultra-marathon runners, in which the pooled estimate was 65.6 %. Time-loss injury proportions between different populations of runners ranged from 3.2 % in cross-country runners to 84.9 % in novice runners. Overall, the proportions were highest among short-distance track runners and ultra-marathon runners. _Limitations:_ The results were pooled by stratification of studies according to the population, injury definition and follow-up/recall period; however, heterogeneity was high. _Conclusions:_ Large differences in injury proportions between different populations of runners existed. Injury proportions were affected by the duration of follow-up. A U-shaped pattern between the running distance and the time-loss injury proportion seemed to exist. Future prospective studies of injury surveillance are highly recommended to take running exposure and censoring into account

Dietary diversity affects feeding behaviour of suckling piglets

Stimulating solid feed intake in suckling piglets is important to facilitate the weaning transition, exemplified by the positive correlation between pre- and post-weaning feed intake. The present study compared the effect of dietary diversity (i.e. offering two feeds simultaneously) and flavour novelty (i.e. regularly changing the flavour of one feed) on the feeding behaviour and performance of suckling piglets until weaning at day 22. It was hypothesized that presentation of the feed in a more diverse form, by varying multiple sensory properties of the feed, stimulates pre-weaning feed intake. Piglets received ad libitum feed from 2 days of age in two feeders per pen (choice feeding set-up). One group of piglets (dietary diversity (DD), n = 10 litters) were given feed A and feed B which differed in production method, size, flavour, ingredient composition and nutrient profile, smell, texture and colour. The other group of piglets (flavour novelty (FN), n = 9 litters) received feed A plus feed A to which one of 4 flavours were added from day 6 in a daily sequential order. Feeding behaviour was studied by weighing feed remains (d6, 12, 16, 22) and by live observations (4-min scan sampling, 6 h/d; d9, 14, 21; n = 6 litters per treatment). Observations were also used to discriminate ‘eaters’ from ‘non-eaters’. All piglets were weighed at d2, 6 and 22. Piglets did not prefer feed A (d2–22: 1.4 ± 0.16 kg/litter) over B (1.6 ± 0.18) within DD nor had a preference for feed A with (d6–22: 1.1 ± 0.06 kg/litter) or without additional flavours (0.9 ± 0.07) within FN. Nevertheless, DD-litters (d2–22: 3.0 ± 0.32 kg) ate significantly more than FN-litters (2.0 ± 0.12 kg; P = 0.02) and explored the feed 2.6 times more at d14 (P = 0.001). Furthermore feed A, the common feed provided in DD and FN, was more consumed in DD (d2–22: 1.4 ± 0.16 kg) compared to FN (1.0 ± 0.07 kg; P = 0.04). The percentage of eaters within a litter did not differ over time between DD (d9: 26%, d14: 78%, d21: 94%) and FN (20%, 71% and 97%) and no effect was found on pre-weaning weight gain. In conclusion, this study showed that provision of dietary diversity to suckling piglets stimulated their feed exploration and intake more than dietary flavour novelty only, but did not enhance the percentage of piglets within a litter that consume the feed or their growth performance. These data suggest that dietary diversity could be an innovative feeding strategy to stimulate solid feed intake in suckling piglets.</p

Quantitative DCE-MRI demonstrates increased blood perfusion in Hoffa’s fat pad signal abnormalities in knee osteoarthritis, but not in patellofemoral pain

Objective: Infrapatellar fat pad (IPFP) fat-suppressed T2 (T2FS) hyperintense regions on MRI are an important imaging feature of knee osteoarthritis (OA) and are thought to represent inflammation. These regions are also common in non-OA subjects, and may not always be linked to inflammation. Our aim was to evaluate quantitative blood perfusion parameters, as surrogate measure of inflammation, within T2FS-hyperintense regions in patients with OA, with patellofemoral pain (PFP) (supposed OA precursor), and control subjects. Methods: Twenty-two knee OA patients, 35 PFP patients and 43 healthy controls were included and underwent MRI, comprising T2 and DCE-MRI sequences. T2FS-hyperintense IPFP regions were delineated and a reference region was drawn in adjacent IPFP tissue with normal signal intensity. After fitting the extended Tofts pharmacokinetic model, quantitative DCE-MRI perfusion parameters were compared between the two regions within subjects in each subgroup, using a paired Wilcoxon signed-rank test. Results: T2FS-hyperintense IPFP regions were present in 16 of 22 (73%) OA patients, 13 of 35 (37%) PFP patients, and 14 of 43 (33%) controls. DCE-MRI perfusion parameters were significantly different between regions with and without a T2FS-hyperintense signal in OA patients, demonstrating higher Ktrans compared to normal IFPF tissue (0.039 min−1 versus 0.025 min−1, p = 0.017) and higher Ve (0.157 versus 0.119, p = 0.010). For PFP patients and controls no significant differences were found. Conclusions: IPFP T2FS-hyperintense regions are associated with higher perfusion in knee OA patients in contrast to identically appearing regions in PFP patients and controls, pointing towards an inflammatory pathogenesis in OA only. Key Points: • Morphologically identical appearing T2FS-hyperintense infrapatellar fat pad regions show different perfusion in healthy subjects, subjects with patellofemoral pain, and subjects with knee osteoarthritis. • Elevated DCE-MRI perfusion parameters within T2FS-hyperintense infrapatellar fat pad regions in patients with osteoarthritis suggest an inflammatory pathogenesis in osteoarthritis, but not in patellofemoral pain and healthy subjects

Reasons and predictors of discontinuation of running after a running program for novice runners

Objectives: To determine the proportion of participants of a running program for novice runners that discontinued running and investigate the main reasons to discontinue and characteristics associated with discontinuation. Design: Prospective cohort study. Methods: The study included 774 participants of Start to Run, a 6-week running program for novice runners. Before the start of the program, participants filled-in a baseline questionnaire to collect information on demographics, physical activity and perceived health. The 26-weeks follow-up questionnaire was used to obtain information on the continuation of running (yes/no) and main reasons for discontinuation. To determine predictors for discontinuation of running, multivariable logistic regression was performed. Results: Within 26 weeks after the start of the 6-week running program, 29.5% of the novice runners (n = 225) had stopped running. The main reason for discontinuation was a running-related injury (n = 108, 48%). Being female (OR 1.74; 95% CI 1.13–2.68), being unsure about the continuation of running after the program (OR 2.06; 95% CI 1.31–3.24) and (almost) no alcohol use (OR 1.62; 95%CI 1.11–2.37) were associated with a higher chance of discontinuation of running. Previous running experience less than one year previously (OR 0.46; 95% CI 0.26–0.83) and a higher score on the RAND-36 subscale physical functioning (OR 0.98; 95% CI 0.96–0.99) were associated with a lower chance of discontinuation. Conclusions: In this group of novice runners, almost one-third stopped running within six months. A running-related injury was the main reason to stop running. Women with a low perceived physical functioning and without running experience were prone to discontinue running

Critical design considerations for time-to-event endpoints in amyotrophic lateral sclerosis clinical trials

Background: Funding and resources for low prevalent neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) are limited, and optimising their use is vital for efficient drug development. In this study, we review the design assumptions for pivotal ALS clinical trials with time-to-event endpoints and provide optimised settings for future trials. Methods: We extracted design settings from 13 completed placebo-controlled trials. Optimal assumptions were estimated using parametric survival models in individual participant data (n=4991). Designs were compared in terms of sample size, trial duration, drug use and costs. Results: Previous trials overestimated the hazard rate by 18.9% (95% CI 3.4% to 34.5%, p=0.021). The median expected HR was 0.56 (range 0.33–0.66). Additionally, we found evidence for an increasing mean hazard rate over time (Weibull shape parameter of 2.03, 95% CI 1.93 to 2.15, p<0.001), which affects the design and planning of future clinical trials. Incorporating accrual time and assuming an increasing hazard rate at the design stage reduced sample size by 33.2% (95% CI 27.9 to 39.4), trial duration by 17.4% (95% CI 11.6 to 23.3), drug use by 14.3% (95% CI 9.6 to 19.0) and follow-up costs by 21.2% (95% CI 15.6 to 26.8). Conclusions: Implementing distributional knowledge and incorporating accrual at the design stage could achieve large gains in the efficiency of ALS clinical trials with time-to-event endpoints. We provide an open-source platform that helps investigators to make more accurate sample size calculations and optimise the use of their available resources

Quantitative volume and dynamic contrast-enhanced MRI derived perfusion of the infrapatellar fat pad in patellofemoral pain

Background: Patellofemoral pain (PFP) is a common knee condition and possible precursor of knee osteoarthritis (OA). Inflammation, leading to an increased perfusion, or increased volume of the infrapatellar fat pad (IPFP) may induce knee pain. The aim of the study was to compare quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters, as imaging biomarkers of inflammation, and volume of the IPFP between patients with PFP and controls and between patients with and without IPFP edema or joint effusion. Methods: Patients with PFP and healthy controls were included and underwent non-fat suppressed 3D fast-spoiled gradient-echo (FSPGR) and DCE-MRI. Image registration was applied to correct for motion. The IPFP was delineated on FSPGR using Horos software. Volume was calculated and quantitative perfusion parameters were extracted by fitting extended Tofts' pharmacokinetic model. Differences in volume and DCE-MRI parameters between patients and controls were tested by linear regression analyses. IPFP edema and effusion were analyzed identically. Results: Forty-three controls and 35 PFP patients were included. Mean IPFP volume was 26.04 (4.18) mL in control subjects and 27.52 (5.37) mL in patients. Median Ktrans was 0.017 (0.016) min-1 in control subjects and 0.016 (0.020) min-1 in patients. None of the differences in volume and perfusion parameters were statistically significant. Knees with effusion showed a higher perfusion of the IPFP compared to knees without effusion in patients only. Conclusions: The IPFP has been implicated as source of knee pain, but higher DCE-MR blood perfusion, an imaging biomarker of inflammation, and larger volume are not associated with PFP. Patient's knees with effusion showed a higher perfusion, pointing towards inflammation

Rabies Virus Populations in Humans and Mice Show Minor Inter-Host Variability within Various Central Nervous System Regions and Peripheral Tissues

Rabies virus (RABV) has a broad host range and infects multiple cell types throughout the infection cycle. Next-generation sequencing (NGS) and minor variant analysis are powerful tools for studying virus populations within specific hosts and tissues, leading to novel insights into the mechanisms of host-switching and key factors for infecting specific cell types. In this study we investigated RABV populations and minor variants in both original (non-passaged) samples and in vitro-passaged isolates of various CNS regions (hippocampus, medulla oblongata and spinal cord) of a fatal human rabies case, and of multiple CNS and non-CNS tissues of experimentally infected mice. No differences in virus populations were detected between the human CNS regions, and only one non-synonymous single nucleotide polymorphism (SNP) was detected in the fifth in vitro passage of virus isolated from the spinal cord. However, the appearance of this SNP shows the importance of sequencing newly passaged virus stocks before further use. Similarly, we did not detect apparent differences in virus populations isolated from different CNS and non-CNS tissues of experimentally infected mice. Sequencing of viruses obtained from pharyngeal swab and salivary gland proved difficult, and we propose methods for improving sampling

Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype

Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes (n = 274 genes) was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years) sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72. We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies (p = 5.31E-18). Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression (t-test, p = 0.033). We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course (t-test, p = 0.025). Our data are consistent with an oligogenic model of ALS. We provide evidence for a number of entirely novel genetic variants of ALS caused by mutations in RNA-binding proteins. Moreover we show that these mutations act synergistically with each other and with C9ORF72 expansions to modify the clinical phenotype of ALS. A key finding is that this synergy is present only between functionally interacting variants. This work has significant implications for ALS therapy development

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Prognosis for patients with amyotrophic lateral sclerosis: development and validation of a personalised prediction model

Summary Background Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive, fatal motor neuron disease with a variable natural history. There are no accurate models that predict the disease course and outcomes, which complicates risk assessment and counselling for individual patients, stratification of patients for trials, and timing of interventions. We therefore aimed to develop and validate a model for predicting a composite survival endpoint for individual patients with ALS. Methods We obtained data for patients from 14 specialised ALS centres (each one designated as a cohort) in Belgium, France, the Netherlands, Germany, Ireland, Italy, Portugal, Switzerland, and the UK. All patients were diagnosed in the centres after excluding other diagnoses and classified according to revised El Escorial criteria. We assessed 16 patient characteristics as potential predictors of a composite survival outcome (time between onset of symptoms and non-invasive ventilation for more than 23 h per day, tracheostomy, or death) and applied backward elimination with bootstrapping in the largest population-based dataset for predictor selection. Data were gathered on the day of diagnosis or as soon as possible thereafter. Predictors that were selected in more than 70% of the bootstrap resamples were used to develop a multivariable Royston-Parmar model for predicting the composite survival outcome in individual patients. We assessed the generalisability of the model by estimating heterogeneity of predictive accuracy across external populations (ie, populations not used to develop the model) using internal–external cross-validation, and quantified the discrimination using the concordance (c) statistic (area under the receiver operator characteristic curve) and calibration using a calibration slope. Findings Data were collected between Jan 1, 1992, and Sept 22, 2016 (the largest data-set included data from 1936 patients). The median follow-up time was 97·5 months (IQR 52·9–168·5). Eight candidate predictors entered the prediction model: bulbar versus non-bulbar onset (univariable hazard ratio [HR] 1·71, 95% CI 1·63–1·79), age at onset (1·03, 1·03–1·03), definite versus probable or possible ALS (1·47, 1·39–1·55), diagnostic delay (0·52, 0·51–0·53), forced vital capacity (HR 0·99, 0·99–0·99), progression rate (6·33, 5·92–6·76), frontotemporal dementia (1·34, 1·20–1·50), and presence of a C9orf72 repeat expansion (1·45, 1·31–1·61), all p<0·0001. The c statistic for external predictive accuracy of the model was 0·78 (95% CI 0·77–0·80; 95% prediction interval [PI] 0·74–0·82) and the calibration slope was 1·01 (95% CI 0·95–1·07; 95% PI 0·83–1·18). The model was used to define five groups with distinct median predicted (SE) and observed (SE) times in months from symptom onset to the composite survival outcome: very short 17·7 (0·20), 16·5 (0·23); short 25·3 (0·06), 25·2 (0·35); intermediate 32·2 (0·09), 32·8 (0·46); long 43·7 (0·21), 44·6 (0·74); and very long 91·0 (1·84), 85·6 (1·96). Interpretation We have developed an externally validated model to predict survival without tracheostomy and non-invasive ventilation for more than 23 h per day in European patients with ALS. This model could be applied to individualised patient management, counselling, and future trial design, but to maximise the benefit and prevent harm it is intended to be used by medical doctors only. Funding Netherlands ALS Foundation