The multiple links between actin and mitochondria.

Actin plays many well-known roles in cells, and understanding any specific role is often confounded by the overlap of multiple actin-based structures in space and time. Here, we review our rapidly expanding understanding of actin in mitochondrial biology, where actin plays multiple distinct roles, exemplifying the versatility of actin and its functions in cell biology. One well-studied role of actin in mitochondrial biology is its role in mitochondrial fission, where actin polymerization from the endoplasmic reticulum through the formin INF2 has been shown to stimulate two distinct steps. However, roles for actin during other types of mitochondrial fission, dependent on the Arp2/3 complex, have also been described. In addition, actin performs functions independent of mitochondrial fission. During mitochondrial dysfunction, two distinct phases of Arp2/3 complex-mediated actin polymerization can be triggered. First, within 5 min of dysfunction, rapid actin assembly around mitochondria serves to suppress mitochondrial shape changes and to stimulate glycolysis. At a later time point, at more than 1 h post-dysfunction, a second round of actin polymerization prepares mitochondria for mitophagy. Finally, actin can both stimulate and inhibit mitochondrial motility depending on the context. These motility effects can either be through the polymerization of actin itself or through myosin-based processes, with myosin 19 being an important mitochondrially attached myosin. Overall, distinct actin structures assemble in response to diverse stimuli to affect specific changes to mitochondria.

Lactate activates the mitochondrial electron transport chain independently of its metabolism.

Lactate has long been considered a cellular waste product. However, we found that as extracellular lactate accumulates, it also enters the mitochondrial matrix and stimulates mitochondrial electron transport chain (ETC) activity. The resulting increase in mitochondrial ATP synthesis suppresses glycolysis and increases the utilization of pyruvate and/or alternative respiratory substrates. The ability of lactate to increase oxidative phosphorylation does not depend on its metabolism. Both L- and D-lactate are effective at enhancing ETC activity and suppressing glycolysis. Furthermore, the selective induction of mitochondrial oxidative phosphorylation by unmetabolized D-lactate reversibly suppressed aerobic glycolysis in both cancer cell lines and proliferating primary cells in an ATP-dependent manner and enabled cell growth on respiratory-dependent bioenergetic substrates. In primary T cells, D-lactate enhanced cell proliferation and effector function. Together, these findings demonstrate that lactate is a critical regulator of the ability of mitochondrial oxidative phosphorylation to suppress glucose fermentation.

Long-term effects of non-pharmaceutical interventions on total disease burden in parsimonious epidemiological models.

The recent global COVID-19 pandemic resulted in governments enacting non-pharmaceutical interventions (NPIs) targeted at reducing transmission of SARS-CoV-2. But the NPIs also affected the transmission of viruses causing non-target seasonal respiratory diseases, including influenza and respiratory syncytial virus (RSV). In many countries, the NPIs were found to reduce cases of such seasonal respiratory diseases, but there is also evidence that subsequent relaxation of NPIs led to outbreaks of these diseases that were larger than pre-pandemic ones, due to the accumulation of susceptible individuals prior to relaxation. Therefore, the net long-term effects of NPIs on the total disease burden of non-target diseases remain unclear. Knowledge of this is important for infectious disease management and maintenance of public health. In this study, we shed light on this issue for the simplified scenario of a set of NPIs that prevent or reduce transmission of a seasonal respiratory disease for about a year and are then removed, using mathematical analyses and numerical simulations of a suite of four epidemiological models with varying complexity and generality. The model parameters were estimated using empirical data pertaining to seasonal respiratory diseases and covered a wide range. Our results showed that NPIs reduced the total disease burden of a non-target seasonal respiratory disease in the long-term. Expressed as a percentage of population size, the reduction was greater for larger values of the basic reproduction number and the immunity loss rate, reflecting larger outbreaks and hence more infections averted by imposition of NPIs. Our study provides a foundation for exploring the effects of NPIs on total disease burden in more-complex scenarios.

Emergency department triage decision-making by registered nurses: An instrument development study.

AIM: To develop and psychometrically test the triage decision-making instrument, a tool to measure Emergency Department Registered Nurses decision-making. DESIGN: Five phases: (1) defining the concept, (2) item generation, (3) face validity, (4) content validity and (5) pilot testing. METHODS: Concept definition informed by a grounded theory study from which four domains emerged. Items relevant to the four domains were generated and revised. Face validity was established using three focus groups. The target population upon which the reliability and validity of the triage decision-making instrument was explored were triage registered nurses in emergency departments. Three expert judges assessed 89 items for content and domain designation using a 4-point scale. Psychometric properties were assessed by exploratory factor analysis, following which the names of the four domains were modified. RESULTS: The triage decision-making instrument is a 22-item tool with four factors: clinical judgement, managing acuity, professional collaboration and creating space. Focus group data indicated support for the domains. Expert review resulted in 46 items with 100% agreement and 13 with 66% agreement. Fifty-nine items were distributed to a convenience sample of 204 triage nurses from six hospitals in 2019. The Kaiser-Meyer-Olkin measures indicated that the data were sufficient for exploratory factor analysis. Bartlett's test indicated patterned relationships among the items (X2 (231) = 1156.69). An eigenvalue of >1.0 was used and four factors explained 48.64% of the variance. All factor loadings were ≥0.40. Internal consistency was demonstrated by Cronbach's alphas of .596 factor 1, .690 factor 2, .749 factor 3 and .822 for factor 4. CONCLUSION: The triage decision-making instrument meets the criteria for face validity, content validity and internal consistency. It is suitable for further testing and refinement. IMPACT: The instrument is a first step in quantifying triage decision-making in real-world clinical environments. The triage decision-making instrument can be used for targeted triage interventions aimed at improving throughput and staff education. STATISTICAL SUPPORT: Dr. Tak Fung who is a member of the research team is a statistician. STATISTICAL METHODS: Development, validation and assessment of instruments/scales. Descriptive statistics. REPORTING METHOD: STROBE cross-sectional checklist. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: The TDI makes the complexity of triage decision-making visible. Identifying the influence of decision-making factors in addition to acuity that affect triage decisions will enable nurse managers and educators to develop targeted interventions and staff development initiatives. By extension, this will enhance patient care and safety.

Improving the realism of neutral ecological models by incorporating transient dynamics with temporal changes in community size.

Neutral models in ecology assume that all species are demographically equivalent, such that their abundances differ ultimately because of demographic stochasticity rather than selection. In spite of their simplicity, neutral models have been found to accurately reproduce static patterns of biodiversity for diverse communities. However, the same neutral models have been found to exhibit species abundance dynamics that are far too slow compared to reality, resulting in poor fits to temporally dynamic patterns of biodiversity. Here, we show that one of the root causes of these slow dynamics is the additional assumption that a community has reached an equilibrium with a fixed community size, with species that have a net growth rate close to zero. We removed this additional assumption by constructing and analyzing a neutral model with an expected community size that can change over time and is not necessarily at equilibrium, which thus allows the historical formation of a community to be represented explicitly. Our analysis demonstrated that for the general scenario where a small community rapidly grows in size to a carrying capacity, representing recovery from ecological disturbance or assembly of a new community, the model produced much larger changes in species abundances and much shorter species ages than a neutral model at an equilibrium with fixed community size. In addition, the species abundance distribution was biphasic with a subset of abundant species arising from a founder effect. We confirmed these new results in applications of the new model to the specific scenario of recovery of the Amazon tree community after the end-Cretaceous bolide impact, which involved periods of increasing and decreasing community size. We conclude that incorporating transient dynamics in neutral models improves realism by allowing explicit consideration of how a community is formed over realistic time-scales.

Temporary Cross-Immunity as a Plausible Driver of Asynchronous Cycles of Dengue Serotypes.

Many infectious diseases exist as multiple variants, with interactions between variants potentially driving epidemiological dynamics. These diseases include dengue, which infects hundreds of millions of people every year and exhibits complex multi-serotype dynamics. Antibodies produced in response to primary infection by one of the four dengue serotypes can produce a period of temporary cross-immunity (TCI) to infection by other serotypes. After this period, the remaining antibodies can facilitate the entry of heterologous serotypes into target cells, thus enhancing severity of secondary infection by a heterologous serotype. This represents antibody-dependent enhancement (ADE). In this study, we analyze an epidemiological model to provide novel insights into the importance of TCI and ADE in producing cyclic outbreaks of dengue serotypes. Our analyses reveal that without TCI, such cyclic outbreaks are synchronous across serotypes and only occur when ADE produces high transmission rates. In contrast, the presence of TCI allows asynchronous cycles of serotypes by inducing a time lag between recovery from primary infection by one serotype and secondary infection by another, with such cycles able to occur without ADE. Our results suggest that TCI is a fundamental driver of asynchronous cycles of dengue serotypes and possibly other multi-variant diseases.

Endoscopic submucosal dissection for colorectal polyps: outcome determining factors.

BACKGROUND: Endoscopic submucosal dissection (ESD) has gained increasing popularity in the management of complicated colorectal polyps. However, clinical outcomes for ESD have remained highly inconsistent worldwide. This study investigated and analysed factors that significantly affect ESD outcomes. METHODS: We conducted a single-centred retrospective study on 220 colorectal polyps removed by ESD from 1st January 2016 to 31st December 2020. Data were collected and retrieved from clinical records. Variables studied included patient demographics, ESD technicalities and polyp characteristics. The primary outcome was completeness of resection based on en bloc and R0 resection rates. The secondary outcomes were recurrence, complications and hospital stay. Further analysis was performed for significant outcome determining factors. RESULTS: The en bloc resection and R0 resection rates were 97.3% and 65% respectively. Intraprocedural and delayed perforation rates were 3.2% and 0.5% respectively. Intraprocedural and delayed bleeding rates were both 1.8%. Post-polypectomy syndrome rate was 2.7%. The median hospital stay was 4 days. Submucosal fibrosis was a significant determining factor for lower en bloc resection (p = 0.004), lower R0 resection (p = 0.002), intraprocedural perforation (p = 0.001), intraprocedural bleeding (p = 0.025) and post-polypectomy syndrome (p = 0.039). Hybrid snaring was associated with lower en bloc resection (p < 0.001), while longer ESD time was associated with lower R0 resection (p = 0.003) and post-polypectomy syndrome (p = 0.025). Other significant factors for post-polypectomy syndrome included young age (p = 0.021) and large polyp size (p = 0.018). Secondary analysis showed that submucosal fibrosis was significantly associated with non-granular lesions (p < 0.001) and prior biopsy (p = 0.003). CONCLUSION: Submucosal fibrosis, hybrid snaring, ESD time, age and polyp size were significant outcome determining factors for ESD. By identifying these factors, strategies may be formulated to improve ESD outcomes.

Regulation of INF2-mediated actin polymerization through site-specific lysine acetylation of actin itself.

INF2 is a formin protein that accelerates actin polymerization. A common mechanism for formin regulation is autoinhibition, through interaction between the N-terminal diaphanous inhibitory domain (DID) and C-terminal diaphanous autoregulatory domain (DAD). We recently showed that INF2 uses a variant of this mechanism that we term "facilitated autoinhibition," whereby a complex consisting of cyclase-associated protein (CAP) bound to lysine-acetylated actin (KAc-actin) is required for INF2 inhibition, in a manner requiring INF2-DID. Deacetylation of actin in the CAP/KAc-actin complex activates INF2. Here we use lysine-to-glutamine mutations as acetylmimetics to map the relevant lysines on actin for INF2 regulation, focusing on K50, K61, and K328. Biochemically, K50Q- and K61Q-actin, when bound to CAP2, inhibit full-length INF2 but not INF2 lacking DID. When not bound to CAP, these mutant actins polymerize similarly to WT-actin in the presence or absence of INF2, suggesting that the effect of the mutation is directly on INF2 regulation. In U2OS cells, K50Q- and K61Q-actin inhibit INF2-mediated actin polymerization when expressed at low levels. Direct-binding studies show that the CAP WH2 domain binds INF2-DID with submicromolar affinity but has weak affinity for actin monomers, while INF2-DAD binds CAP/K50Q-actin 5-fold better than CAP/WT-actin. Actin in complex with full-length CAP2 is predominately ATP-bound. These interactions suggest an inhibition model whereby CAP/KAc-actin serves as a bridge between INF2 DID and DAD. In U2OS cells, INF2 is 90-fold and 5-fold less abundant than CAP1 and CAP2, respectively, suggesting that there is sufficient CAP for full INF2 inhibition.

Factors Associated with Quality of Life in Adults with Persistent Post-Concussion Symptoms.

OBJECTIVE: To assess demographic, clinical, and injury characteristics associated with health-related quality of life (HRQOL) in adults with persistent post-concussion symptoms (PPCS). METHODS: Adults with PPCS presenting to a specialized brain injury clinic completed demographic, injury, and clinical outcome questionnaires at the initial clinic assessment. Clinical outcome measures were collected including the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder Scale-7 (GAD-7), and the Fatigue Severity Scale (FSS). HRQOL was measured using the Quality of Life after Brain Injury (QOLIBRI) questionnaire. Stepwise hierarchical multiple regression analysis adjusting for age, sex, and months since injury was used to determine associations between quality of life and clinical outcome measures. RESULTS: Overall, 125 participants were included. The PHQ-9, FSS, and GAD-7 were significant predictors of QOLIBRI scores (R2 = 0.481, p < .001), indicating that participants with higher levels of depressive symptoms, fatigue, and anxiety reported poorer HRQOL. The PHQ-9 score was the strongest predictor, accounting for 42.0% of the variance in QOLIBRI scores. No demographic or injury characteristics significantly predicted QOLIBRI scores. There was a high prevalence of depressive symptoms with 72.8% of participants having PHQ-9 scores ≥ 10. CONCLUSION: Among patients with PPCS, mental health and fatigue are important contributors to HRQOL. As there is a high burden of mood disorders and fatigue in this population, targeted treatments for these concerns may impact the quality of life.

Two distinct actin filament populations have effects on mitochondria, with differences in stimuli and assembly factors.

Recent studies show that mitochondria and actin filaments work together in two contexts: (1) increased cytoplasmic calcium induces cytoplasmic actin polymerization that stimulates mitochondrial fission and (2) mitochondrial depolarization causes actin assembly around mitochondria, with roles in mitophagy. It is unclear whether these two processes utilize similar actin assembly mechanisms. Here, we show that these are distinct actin assembly mechanisms in the acute phase after treatment (<10 min). Calcium-induced actin assembly is INF2 dependent and Arp2/3 complex independent, whereas depolarization-induced actin assembly is Arp2/3 complex dependent and INF2 independent. The two types of actin polymerization are morphologically distinct, with calcium-induced filaments throughout the cytosol and depolarization-induced filaments as 'clouds' around depolarized mitochondria. We have previously shown that calcium-induced actin stimulates increases in both mitochondrial calcium and recruitment of the dynamin GTPase Drp1 (also known as DNM1L). In contrast, depolarization-induced actin is temporally associated with extensive mitochondrial dynamics that do not result in mitochondrial fission, but in circularization of the inner mitochondrial membrane (IMM). These dynamics are dependent on the protease OMA1 and independent of Drp1. Actin cloud inhibition causes increased IMM circularization, suggesting that actin clouds limit these dynamics.This article has an associated First Person interview with the first author of the paper.

Characterizing Physical Activity and Sedentary Behavior in Adults With Persistent Postconcussive Symptoms After Mild Traumatic Brain Injury.

OBJECTIVE: To evaluate physical activity (PA) and sedentary behavior and their associations with symptom and quality of life outcomes in adults with persistent postconcussive symptoms (PPCS) after mild traumatic brain injury (mTBI). DESIGN: Cross-sectional cohort study. SETTING: Outpatient brain injury clinic. PARTICIPANTS: Consecutive sample of adults (N=180) with a diagnosis of mTBI and PPCS. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: PA and sedentary behavior were assessed using the Godin Leisure-Time Exercise Questionnaire and Rapid Assessment Disuse Index, respectively. Participants were dichotomized according to whether they completed 150 minutes of moderate-to-vigorous PA per week, based on Canadian guidelines. Postinjury moderate-to-vigorous PA was also analyzed as a continuous variable. RESULTS: Prior to injury, 85% of participants reported meeting PA guidelines, compared with 28% postinjury. Individuals meeting PA guidelines postinjury reported higher quality of life (η2p=0.130; P<.001) and lower scores on measures of functional impact of headache (η2p=0.065; P=.009), fatigue (η2p=0.080; P=.004), depression (η2p=0.085; P=.001), and anxiety (η2p=0.046; P=.031), compared with those not meeting guidelines. Sedentary behavior postinjury was negatively correlated with quality of life (rs[127]=-0.252; P=.004) and positively correlated with symptom burden (rs[167]=0.227; P=.003), fatigue (rs[127]=0.288; P=.001), depression (rs[174]=0.319; P<.001), and anxiety (rs[127]=0.180; P=.042). CONCLUSIONS: PA was significantly decreased in individuals with PPCS compared to preinjury levels. Meeting PA guidelines postinjury was associated with better clinical outcomes, suggesting that returning individuals to PA should be considered in the treatment of this patient population.

Predictors of morbidity related to stoma closure after colorectal cancer surgery.

PURPOSE: A defunctioning stoma is essential in reducing symptomatic leakage after colorectal surgery, particularly after lower anterior resection. Subsequent stoma closure is associated with morbidity and rarely mortality. This study aimed to identify the risk factors associated with post-operative complications related to stoma closure. METHODS: This retrospective cohort included patients who have undergone elective stoma closure between 2015 and 2017. Patient demographics, pre-morbidities, use of systemic therapy, stoma characteristics, and post-operative complications were retrieved from electronic records. Univariate and multivariate analysis was carried out to identify risk factors of stoma closure related morbidity. RESULTS: Ninety patients were included with a median age of 65 years, of which 58 (64.4%) of them were male. Sixty-nine (76.7%) patients had loop colostomy, while the rest had loop ileostomy. Fifty-four (60%) patients received neoadjuvant or adjuvant therapy. The median time interval from stoma creation to closure was 15 months. Nineteen (21.1%) patients had post-operative complications. The two most commonly observed post-operative complications were wound complications (16.7%) and intra-abdominal collections (6.7%). Fifteen (16.7%) patients developed an incisional hernia. The median follow-up time was 29 months. There was no 30-day mortality in this cohort. In multivariate analysis, adjuvant chemotherapy was associated with a higher risk of wound complications (p = 0.027). Higher risk of incisional hernia was seen in patients with history of hypertension (p = 0.046), use of adjuvant chemotherapy (p = 0.042) and stoma-related complications before closure (p = 0.002). Male patients might be associated with a higher risk of incisional hernia. CONCLUSION: Adjuvant chemotherapy is associated with a higher risk of post-operative complications, particularly with wound complications. Male patients, hypertension, adjuvant chemotherapy, and stoma-related complications are associated with a higher risk of incisional hernia.

Essential anatomy for total mesorectal excision and lateral lymph node dissection, in both trans-abdominal and trans-anal perspective.

BACKGROUND AND PURPOSE: Total Mesorectal Excisions (TME) is the standard treatment of rectal cancer. It can be performed under laparoscopic, robotic or transanal approach. Inadvertent injury to surrounding structure like autonomic nerves is avoidable, no matter which approach is adopted. Lateral lymph node dissection (LLND) is a less commonly performed pelvic operation involving dissection in an unfamiliar area to most general surgeons. This article aims to clarify all the essential anatomy related to these procedures. METHODS: We performed thorough literature search and revision on the pelvic anatomy. Our cases of TME and LLND, under either laparoscopic or transanal approach, were reviewed. We integrated the knowledge from literatures and our own experience. The result was presented in details, together with original figures and intra-operative photos. MAIN FINDINGS: Anatomy of pelvic fascia, autonomic nerve system, anal canal and sphincter complex are core knowledge in performing TME and LLND. CONCLUSIONS: Thorough understanding of the pelvic anatomy enables colorectal surgeons to master these procedures, avoid complication and perform extended resection. On the other hand, surgeons can appreciate the complex pelvic anatomy easier by seeing the pelvis in opposite angles (transabdominal and transaanal view).

Invasion growth rate and its relevance to persistence: a response to Technical Comment by Ellner et al.

Ellner et al. (2020) state that identifying the mechanisms producing positive invasion growth rates (IGR) is useful in characterising species persistence. We agree about the importance of the sign of IGR as a binary indicator of persistence, but question whether its magnitude provides much information once the sign is given.

Mean growth rate when rare is not a reliable metric for persistence of species.

The coexistence of many species within ecological communities poses a long-standing theoretical puzzle. Modern coexistence theory (MCT) and related techniques explore this phenomenon by examining the chance of a species population growing from rarity in the presence of all other species. The mean growth rate when rare, E [ r ] , is used in MCT as a metric that measures persistence properties (like invasibility or time to extinction) of a population. Here we critique this reliance on E [ r ] and show that it fails to capture the effect of temporal random abundance variations on persistence properties. The problem becomes particularly severe when an increase in the amplitude of stochastic temporal environmental variations leads to an increase in E [ r ] , since at the same time it enhances random abundance fluctuations and the two effects are inherently intertwined. In this case, the chance of invasion and the mean extinction time of a population may even go down as E [ r ] increases.

Temporal population variability in local forest communities has mixed effects on tree species richness across a latitudinal gradient.

Among the local processes that determine species diversity in ecological communities, fluctuation-dependent mechanisms that are mediated by temporal variability in the abundances of species populations have received significant attention. Higher temporal variability in the abundances of species populations can increase the strength of temporal niche partitioning but can also increase the risk of species extinctions, such that the net effect on species coexistence is not clear. We quantified this temporal population variability for tree species in 21 large forest plots and found much greater variability for higher latitude plots with fewer tree species. A fitted mechanistic model showed that among the forest plots, the net effect of temporal population variability on tree species coexistence was usually negative, but sometimes positive or negligible. Therefore, our results suggest that temporal variability in the abundances of species populations has no clear negative or positive contribution to the latitudinal gradient in tree species richness.

Janzen-Connell Effects Are a Weak Impediment to Competitive Exclusion.

AbstractA goal of ecology is to identify the stabilizing mechanisms that maintain species diversity in the face of competitive exclusion and drift. For tropical forest tree communities, it has been hypothesized that high diversity is maintained via Janzen-Connell effects, whereby host-specific natural enemies prevent any one species from becoming too abundant. Here we explore the plausibility of this hypothesis with theoretical models. We confirm a previous result that when added to a model with drift but no competitive exclusion-that is, a neutral model where intrinsic fitnesses are perfectly equalized across species-Janzen-Connell effects maintain very high species richness that scales strongly with community size. However, when competitive exclusion is introduced-that is, when intrinsic fitnesses vary across species-the number of species maintained by Janzen-Connell effects is substantially reduced and scales much less strongly with community size. Because fitness variation is pervasive in nature, we conclude that the potential of Janzen-Connell effects to maintain diversity is probably weak and that the mechanism does not yet provide a sufficient explanation for the observed high diversity of tropical forest tree communities. We also show that, surprisingly, dispersal limitation can further reduce the ability of Janzen-Connell effects to maintain diversity.

Probability distributions of extinction times, species richness, and immigration and extinction rates in neutral ecological models.

In community ecology, neutral models make the assumption that species are equivalent, such that species abundances differ only because of demographic stochasticity. Despite their ecological simplicity, neutral models have been found to give reasonable descriptions of expected patterns of biodiversity in communities with many species. Such patterns include the expected total number of species and species-abundance distributions describing the expected number of species in different abundance classes. However, the expected patterns represent only the central tendencies of the full distributions of possible outcomes. Thus, ecological inferences and conclusions based only on expected patterns are incomplete, and may be misleading. Here, we address this issue for the spatially implicit neutral model, by using classic results from birth-death processes to derive (1) the probability distribution of extinction time of a species with given abundance for the metacommunity; (2) the probability distributions of total species richness and number of species with given abundance for both the metacommunity and local community; and (3) the probability distributions of the average immigration and extinction rates in the local community, across different values of total species richness. We illustrate the utility of these probability distributions in providing greater ecological insight via statistical inference. Firstly, we show that under the neutral metacommunity model, there is only 2.65×10-9 probability that the age of a common tree species in the Amazon is  ≤ 3  × 108 yr, which is approximately the oldest estimated age of the first angiosperm. Thus, species ages from the model are unrealistically high. Secondly, for a tree community in a 50 ha plot at Barro Colorado Island in Panama, we show that the spatially implicit model can be fitted to observed species richness and an independent estimate of the immigration parameter, with the fitted model predicting a species-abundance distribution close to the observed distribution. Our results complement those using sampling formulae that specify the multivariate probability distribution of species abundances from neutral models.

Improving symptom burden in adults with persistent post-concussive symptoms: a randomized aerobic exercise trial protocol.

BACKGROUND: Persistent post-concussive symptoms (PPCS) affect up to 30% of individuals following mild traumatic brain injury. PPCS frequently includes exercise intolerance. Sub-symptom threshold aerobic exercise has been proposed as a treatment option for symptom burden and exercise intolerance in this population. The primary aim of this study is to evaluate whether a progressive, sub-symptom threshold aerobic exercise program can alleviate symptom burden in adults with PPCS. METHODS: Fifty-six adults (18-65) with PPCS (>3mos-5 yrs) will be randomized into two groups: an immediate start 12-week aerobic exercise protocol (AEP) or delayed start 6-week placebo-like stretching protocol (SP), followed by AEP. Aerobic or stretching activities will be completed 5x/week for 30 mins during the intervention. Online daily activity logs will be submitted. Exercise prescriptions for the AEP will be 70-80% of heart rate at the point of symptom exacerbation achieved on a treadmill test with heart rate monitoring. Exercise prescription will be updated every 3-weeks with a repeat treadmill test. The Rivermead Post-concussion Symptom Questionnaire will be the primary outcome measure at 6 and 12-weeks of intervention. Secondary outcomes include assessments of specific symptoms (headache, quality of life, mood, anxiety, fatigue, dizziness, sleep parameters, daytime sleepiness) in addition to blood biomarkers and magnetic resonance imaging and spectroscopy data for quantification of brain metabolites including γ-aminobutyric acid (GABA), glutathione, glutamate and N-acetyl aspartate (NAA) all measured at 6 and 12-weeks of intervention. DISCUSSION: This trial will evaluate the use of aerobic exercise as an intervention for adults with PPCS, thus expanding our knowledge of this treatment option previously studied predominantly for adolescent sport-related concussion. TRIAL REGISTRATION: ClinicalTrials.gov - NCT03895450 (registered 2019-Feb-11).