A community health-coaching referral program following discharge from treatment for chronic low back pain - a qualitative study of the patient's perspective.

BACKGROUND: Global policy and guidelines for low back pain (LBP) management promote physical activity and self-management yet adherence is poor and a decline in outcomes is common following discharge from treatment. Health coaching is effective at improving exercise adherence, self-efficacy, and social support in individuals with chronic conditions, and may be an acceptable, cost-effective way to support people in the community following discharge from treatment for LBP. AIM: This qualitative study aimed to understand which aspects of a community over-the-phone health-coaching program, were liked and disliked by patients as well as their perceived outcomes of the service after being discharged from LBP treatment. METHODS: A purposive sampling approach was used to recruit 12 participants with chronic LBP, from a large randomised controlled trial, who were randomly allocated to receive a health coaching program from the Get Healthy Service® in Australia. Semi-structured interviews were conducted, and a general inductive thematic analysis approach was taken. RESULTS: The main themes uncovered regarding the intervention included the positive and negative aspects of the health coaching service and the relationship between the participant and health coach. Specifically, the participants spoke of the importance of the health coach, the value of goal setting, the quality of the advice received, the benefits of feeling supported, the format of the coaching service, and LBP-specific knowledge. They also reported the health coach and the coaching relationship to be the primary factors influencing the program outcomes and the qualities of the coaching relationship they valued most were connection, communication, care, and competence. The sub-themes uncovered regarding the outcomes of the intervention included positive impacts (a greater capacity to cope, increased confidence, increased motivation and increased satisfaction) and negative impacts (receiving no personal benefit). CLINICAL IMPLICATIONS: In an environment where self-management and self-care are becoming increasingly important, understanding the patient's experience as part of a coaching program is likely to lead to improved quality of health coaching care, more tailored service delivery and potentially more effective and cost-effective community-based care for individuals with chronic LBP in the community after being discharged from treatment. TRIAL REGISTRATION: The GBTH trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12620000889954) on 10/9/2020. Ethical approval was prospectively granted by the Western Sydney Local Health District Human Research and Ethics Committee (2020/ETH00115). Written informed consent was obtained from all participants. The relevant sponsor has reviewed the study protocol and consent form.

Perceived social support impacts on exercise adherence in patients with chronic low back pain.

BACKGROUND: Initiating and maintaining physical activity is particularly difficult for at-risk groups such as those with chronic low back pain (LBP). OBJECTIVE: This study aimed to assess whether there is a relationship between perceived social support (e.g., emotional and physical support) in individuals recently discharged from treatment for chronic LBP and the number of exercise sessions and total amount of exercise they perform over a 6-month period. This study also aimed to investigate a possible mediation effect of exercise self-efficacy on the relationship between perceived social support and exercise adherence (number of exercise sessions and total amount of exercise). METHODS: This prognostic study employed a secondary analysis of data collected for The Buddy Study; Data was collected through online weekly diaries over a 6-month period. Poisson regression analyses were used to quantify the relationship between social support at baseline and total number of exercise sessions, and total amount of exercise performed (frequency and duration) in the 6-month follow-up period. Where a relationship was observed, the Stata SEM command was used for the mediation analysis. RESULTS: A positive relationship was found between participants' perceived levels of social support at baseline and the total number of exercise sessions they performed (IRR = 1.56, 95%CI: 1.18 to 2.06) and the total amount of exercise they performed (IRR = 1.57, 95%CI: 1.05 to 2.35) during the 6-month follow-up period. No mediating relationship was found between exercise self-efficacy at 3-months and the total number of exercise sessions performed (ß 3.96, 95% CI: -4.91 to 12.84), or the total amount of exercise performed (ß 243.96, 95% CI: -258.08 to 746.01). CONCLUSION: Social support is potentially an important aspect of exercise adherence, following discharge from treatment, for those with chronic LBP. People's self-efficacy to exercise does not appear to mediate this relationship. Harnessing social support following physiotherapy treatment may increase exercise adherence and may therefore improve long term outcomes for those with chronic LBP.

Health coaching intervention with or without the support of an exercise buddy to increase physical activity of people with chronic low back pain compared to usual care: a feasibility and pilot randomised controlled trial.

BACKGROUND: Exercise buddies (people to exercise together with) might support people with low back pain (LBP) to become active. However, involving buddies in randomised controlled trials (RCT) might challenge recruitment, data collection and follow-up. OBJECTIVES: To explore the feasibility of the intervention, recruitment and data collection approaches and potential effects of a health coaching intervention (focused on physical activity) with or without exercise buddies' support on physical activity of people with chronic LBP versus usual discharge care. DESIGN: Feasibility and pilot RCT. METHODS: Adults (n = 30) discharged from LBP treatment were randomised to the Buddy-Assisted (health coaching intervention with exercise buddy's support), Individual-Only (health coaching only), or usual care groups. Data were collected at baseline, three and six months. The feasibility of trial's procedures was assessed through recruitment rate (acceptable if >70%), data completion rate (acceptable if ≤ 20% missing data), and follow-up rate (successful if ≥ 85%). The intervention's acceptability was assessed via feedback questionnaires. Preliminary effects on physical activity and other outcomes were also explored. RESULTS: Recruitment and baseline data completion were acceptable. However, data collection and follow-up rates post-randomisation were not. 85% of the Buddy-Assisted Group believed the buddies helped them to increase physical activity and would recommend the intervention. 70% of the Individual-Only and Control groups believed exercise buddies would help them to become further active. CONCLUSION: The data collection and follow-up approaches were not successful and need amending before a large-scale RCT. Nonetheless, the buddy-assisted intervention was well-accepted. A future RCT will focus on differences in clinical outcomes. TRIAL REGISTRATION: The study was registered at the Australian New Zealand Clinical Trial Registry (ACTRN12620001118998).

Trazodone rescues dysregulated synaptic and mitochondrial nascent proteomes in prion neurodegeneration.

The unfolded protein response (UPR) is rapidly gaining momentum as a therapeutic target for protein misfolding neurodegenerative diseases, in which its overactivation results in sustained translational repression leading to synapse loss and neurodegeneration. In mouse models of these disorders, from Alzheimer's to prion disease, modulation of the pathway-including by the licensed drug, trazodone-restores global protein synthesis rates with profound neuroprotective effects. However, the precise nature of the translational impairment, in particular the specific proteins affected in disease, and their response to therapeutic UPR modulation are poorly understood. We used non-canonical amino acid tagging (NCAT) to measure de novo protein synthesis in the brains of prion-diseased mice with and without trazodone treatment, in both whole hippocampus and cell-specifically. During disease the predominant nascent proteome changes occur in synaptic, cytoskeletal and mitochondrial proteins in both hippocampal neurons and astrocytes. Remarkably, trazodone treatment for just 2 weeks largely restored the whole disease nascent proteome in the hippocampus to that of healthy, uninfected mice, predominantly with recovery of proteins involved in synaptic and mitochondrial function. In parallel, trazodone treatment restored the disease-associated decline in synapses and mitochondria and their function to wild-type levels. In conclusion, this study increases our understanding of how translational repression contributes to neurodegeneration through synaptic and mitochondrial toxicity via depletion of key proteins essential for their function. Further, it provides new insights into the neuroprotective mechanisms of trazodone through reversal of this toxicity, relevant for the treatment of neurodegenerative diseases via translational modulation.

Comparison of Tiling Artifact Removal Methods in Secondary Ion Mass Spectrometry Images.

Time-of-flight secondary ion mass spectrometry (ToF-SIMS) imaging is used across many fields for the atomic and molecular characterization of surfaces, with both high sensitivity and high spatial resolution. When large analysis areas are required, standard ToF-SIMS instruments allow for the acquisition of adjoining tiles, which are acquired by rastering the primary ion beam. For such large area scans, tiling artifacts are a ubiquitous challenge, manifesting as intensity gradients across each tile and/or sudden changes in intensity between tiles. Such artifacts are thought to be related to a combination of sample charging, local detector sensitivity issues, and misalignment of the primary ion gun, among other instrumental factors. In this work, we investigated six different computational tiling artifact removal methods: tensor decomposition, multiplicative linear correction, linear discriminant analysis, seamless stitching, simple averaging, and simple interpolating. To ensure robustness in the study, we applied these methods to three hyperspectral ToF-SIMS data sets and one OrbiTrapSIMS data set. Our study includes a carefully designed statistical analysis and a quantitative survey that subjectively assessed the quality of the various methods employed. Our results demonstrate that while certain methods are useful and preferred more often, no one particular approach can be considered universally acceptable and that the effectiveness of the artifact removal method is strongly dependent on the particulars of the data set analyzed. As examples, the multiplicative linear correction and seamless stitching methods tended to score more highly on the subjective survey; however, for some data sets, this led to the introduction of new artifacts. In contrast, simple averaging and interpolation methods scored subjectively poorly on the biological data set, but more highly on the microarray data sets. We discuss and explore these findings in depth and present general recommendations given our findings to conclude the work.

Developing resilient clinical trials: Lessons learned from rolling out the Get Back to Healthy trial during a pandemic.

BACKGROUND: The COVID-19 pandemic has caused wide-spread disruptions to the conduct of randomised controlled trials (RCTs), particularly those involving public health services. Using the Get Back to Healthy trial as an example, this study aimed to contextualise the challenges imposed by the COVID-19 pandemic on implementation of RCTs involving public health services in Australia, summarise the effect of common and novel contingency strategies employed to mitigate these challenges, and describe key lessons learned. METHODS: The main challenges, the effect of contingency strategies employed, and key lessons learned were summarised descriptively. RESULTS: The main COVID-19-related challenge has been slow recruitment due to the suspension of clinical services for the trial target population. This challenge has been addressed through carefully considered adjustments to trial design (i.e., expanding the trial eligibility criteria), which has markedly improved trial recruitment rates. Other challenges have included the rapid transition to remote consent and data collection methods, increased complexity of monitoring participant safety, and future statistical challenges with disentangling the impact of the COVID-19 pandemic from treatment effects. The key lessons learned are: (i) adaptations to trial design may be necessary during a pandemic; (ii) offering remote methods may encourage trial participation from all age groups during a pandemic; (iii) enhanced monitoring of safety is critical during a pandemic; (iv) statistical challenges are likely to occur and should be considered when interpreting trial results. CONCLUSION: Key lessons learned may be useful for informing the conduct of resilient RCTs, particularly those involving public health services, in the present and future.

Effectiveness of a coordinated support system linking public hospitals to a health coaching service compared with usual care at discharge for patients with chronic low back pain: protocol for a randomised controlled trial.

BACKGROUND: Although many people with chronic low back pain (LBP) improve following conservative treatment, one in five will experience worsening symptoms after discharge from treatment and seek health care again. The current LBP clinical care pathway in many health services lacks a well-integrated, systematic approach to support patients to remain physically active and self-manage their symptoms following discharge from treatment. Health coaching can support people to improve physical activity levels and may potentially reduce health care utilisation for LBP. The primary aim of this study is to evaluate the effect of introducing a coordinated support system (linking hospital outpatient physiotherapy services to a public health coaching service) at discharge from LBP treatment, on the future use of hospital, medical, and health services for LBP, compared with usual care provided at discharge. METHODS: Three hundred and seventy-four adults with chronic non-specific LBP will be recruited from the outpatient physiotherapy departments of public hospitals in New South Wales, Australia. Participants will be individually randomised to a support system (n = 187) or usual care group (n = 187). All participants will receive usual care provided at discharge from treatment. Participants allocated to the support system will also receive up to 10 telephone-based health coaching sessions, delivered by the Get Healthy Service®, over a 6-month period. Health coaches will monitor and support participants to improve physical activity levels and achieve personal health-related goals. The primary outcome is the total number of encounters with hospital, medical, and health services for LBP, at 12 months from baseline. A within-trial economic evaluation will quantify the incremental costs and benefits of the support system from a health system perspective, to support reimbursement decision making. DISCUSSION: This study will establish the effect of a coordinated support system, introduced at discharge from treatment, on the future use of hospital, medical, and health services for LBP and various health outcomes. CONCLUSION: Innovative community-driven solutions to support people with chronic LBP after discharge from treatment are urgently needed. Study findings will help inform health care policy and clinical practice in Australia. TRIAL REGISTRATION: Prospectively registered on the Australian New Zealand Clinical Trials Registry ( ACTRN12620000889954 ) on 10/09/2020.

Targeting the kinase insert loop of PERK selectively modulates PERK signaling without systemic toxicity in mice.

Chronic activation of the unfolded protein response (UPR), notably the branch comprising the kinase PERK and the translation initiation factor eIF2α, is a pathological feature of many neurodegenerative diseases caused by protein misfolding. Partial reduction of UPR signaling at the level of phosphorylated eIF2α is neuroprotective and avoids the pancreatic toxicity caused by full inhibition of PERK kinase activity. However, other stress pathways besides the UPR converge on phosphorylated eIF2α in the integrated stress response (ISR), which is critical to normal cellular function. We explored whether partial inhibition of PERK signaling may be a better therapeutic option. PERK-mediated phosphorylation of eIF2α requires its binding to the insert loop within PERK's kinase domain, which is, itself, phosphorylated at multiple sites. We found that, as expected, Akt mediates the phosphorylation of Thr799 in PERK. This phosphorylation event reduced eIF2α binding to PERK and selectively attenuated downstream signaling independently of PERK activity and the broader ISR. Induction of Thr799 phosphorylation with a small-molecule activator of Akt similarly reduced PERK signaling and increased both neuronal and animal survival without measurable pancreatic toxicity in a mouse model of prion disease. Thus, promoting PERK phosphorylation at Thr799 to partially down-regulate PERK-eIF2α signaling while avoiding widespread ISR inhibition may be a safe therapeutic approach in neurodegenerative disease.

A randomized clinical trial comparing the McKenzie method and motor control exercises in people with chronic low back pain and a directional preference: 1-year follow-up.

OBJECTIVE: The primary objective of this study was to compare the long-term (1-year follow-up) effects of the McKenzie method and motor control exercises on trunk muscle thickness in people with chronic low back pain (LBP) and a directional preference. DESIGN: Randomized controlled trial. SETTING: A secondary public health facility in Sydney, Australia. PARTICIPANTS: Seventy adults with greater than 3-month history of LBP and a directional preference. INTERVENTIONS: Participants were randomized to receive 12 treatments of either the McKenzie method or motor control exercises over 8-weeks. OUTCOME MEASURES: Muscle thickness of the transversus abdominis, obliquus internus, and obliquus externus measured from ultrasound images. Secondary outcomes included function, perceived recovery, and pain. Outcomes were collected at baseline, post intervention at 8-weeks, and at 1-year follow-up by blinded assessors. The current paper focuses on the 1-year follow-up. RESULTS: Fifty-eight participants completed data collection for the primary outcome at 1-year. There were no significant between group differences for changes in trunk muscle thickness for any of the three investigated muscles: transversus abdominis [3%, 95% confidence interval (CI): -5%, 11%], obliquus internus [-4%, 95% CI: -9%, 2%] and obliquus externus [3%, 95% CI: -4%, 11%]. Similarly, there were no significant differences between groups for the secondary outcomes of function, perceived recovery and pain. CONCLUSION: Trunk muscle thickness, function, perceive recovery and pain are similar between patients receiving McKenzie method or motor control exercises at a 1-year follow-up in a population of people with chronic LBP and a directional preference. Clinical Trials Registration number CTRN12611000971932.

Treatment Effect Sizes of Mechanical Diagnosis and Therapy for Pain and Disability in Patients With Low Back Pain: A Systematic Review.

BACKGROUND: Mechanical Diagnosis and Therapy (MDT) is a treatment-based classification system founded on 3 core principles: classification into diagnostic syndromes, classification-based intervention, and appropriate application of force. Many randomized controlled trials have investigated the efficacy of MDT for low back pain; however, results have varied. The inconsistent delivery of MDT across trials may explain the different findings. OBJECTIVES: To compare treatment effect sizes for pain or disability between trials that delivered MDT consistent with the core principles of the approach and trials that met some or none of these principles. METHODS: In this systematic review, databases were searched from inception to June 2018 for studies that delivered MDT compared to nonpharmacological, conservative control interventions in patients with low back pain and reported outcomes of pain or disability. Studies were classified as "adherent" (meeting the core principles of MDT) or "nonadherent" (using some or none of the principles of MDT). Data were extracted by 2 independent reviewers. Meta-regression procedures were used to analyze the effect of delivery mode on clinical outcomes, adjusting for covariates of symptom duration (less than or greater than 3 months) and control intervention (minimal or active). RESULTS: Studies classified as adherent to the MDT approach showed greater reductions in pain and disability of 15.0 (95% confidence interval: 7.3, 22.7) and 11.7 (95% confidence interval: 5.4, 18.0) points, respectively, on a 100-point scale compared to nonadherent trials. CONCLUSION: This review provides preliminary evidence that treatment effects of MDT are greater when the core principles are followed. LEVEL OF EVIDENCE: Therapy, level 1a. J Orthop Sports Phys Ther 2019;49(4):219-229. Epub 13 Feb 2019. doi:10.2519/jospt.2019.8734.

Neuronal Mitochondrial Dysfunction Activates the Integrated Stress Response to Induce Fibroblast Growth Factor 21.

Stress adaptation is essential for neuronal health. While the fundamental role of mitochondria in neuronal development has been demonstrated, it is still not clear how adult neurons respond to alterations in mitochondrial function and how neurons sense, signal, and respond to dysfunction of mitochondria and their interacting organelles. Here, we show that neuron-specific, inducible in vivo ablation of the mitochondrial fission protein Drp1 causes ER stress, resulting in activation of the integrated stress response to culminate in neuronal expression of the cytokine Fgf21. Neuron-derived Fgf21 induction occurs also in murine models of tauopathy and prion disease, highlighting the potential of this cytokine as an early biomarker for latent neurodegenerative conditions.

What Is Our Current Understanding of PrPSc-Associated Neurotoxicity and Its Molecular Underpinnings?

The prion diseases are a collection of fatal, transmissible neurodegenerative diseases that cause rapid onset dementia and ultimately death. Uniquely, the infectious agent is a misfolded form of the endogenous cellular prion protein, termed PrPSc. Despite the identity of the molecular agent remaining the same, PrPSc can cause a range of diseases with hereditary, spontaneous or iatrogenic aetiologies. However, the link between PrPSc and toxicity is complex, with subclinical cases of prion disease discovered, and prion neurodegeneration without obvious PrPSc deposition. The toxic mechanisms by which PrPSc causes the extensive neuropathology are still poorly understood, although recent advances are beginning to unravel the molecular underpinnings, including oxidative stress, disruption of proteostasis and induction of the unfolded protein response. This review will discuss the diseases caused by PrPSc toxicity, the nature of the toxicity of PrPSc, and our current understanding of the downstream toxic signaling events triggered by the presence of PrPSc.

Fine-tuning PERK signaling for neuroprotection.

Protein translation and folding are tightly controlled processes in all cells, by proteostasis, an important component of which is the unfolded protein response (UPR). During periods of endoplasmic reticulum stress because of protein misfolding, the UPR activates a coordinated response in which the PERK branch activation restricts translation, while a variety of genes involved with protein folding, degradation, chaperone expression and stress responses are induced through signaling of the other branches. Chronic overactivation of the UPR, particularly the PERK branch, is observed in the brains of patients in a number of protein misfolding neurodegenerative diseases, including Alzheimer's, and Parkinson's diseases and the tauopathies. Recently, numerous genetic and pharmacological studies in mice have demonstrated the effectiveness of inhibiting the UPR for eliciting therapeutic benefit and boosting memory. In particular, fine-tuning the level of PERK inhibition to provide neuroprotection without adverse side effects has emerged as a safe, effective approach. This includes the recent discovery of licensed drugs that can now be repurposed in clinical trials for new human treatments for dementia. This review provides an overview of the links between UPR overactivation and neurodegeneration in protein misfolding disorders. It discusses recent therapeutic approaches targeting this pathway, with a focus on treatments that fine-tune PERK signaling.

Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice.

See Mercado and Hetz (doi:10.1093/brain/awx107) for a scientific commentary on this article.Signalling through the PERK/eIF2α-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is overactivated in brains of patients with Alzheimer’s disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions. Thus, in mouse models of neurodegenerative disease, prolonged overactivation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss. Re-establishing translation rates by inhibition of eIF2α-P activity, genetically or pharmacologically, restores memory and prevents neurodegeneration and extends survival. However, the experimental compounds used preclinically are unsuitable for use in humans, due to associated toxicity or poor pharmacokinetic properties. To discover compounds that have anti-eIF2α-P activity suitable for clinical use, we performed phenotypic screens on a NINDS small molecule library of 1040 drugs. We identified two compounds, trazodone hydrochloride and dibenzoylmethane, which reversed eIF2α-P-mediated translational attenuation in vitro and in vivo. Both drugs were markedly neuroprotective in two mouse models of neurodegeneration, using clinically relevant doses over a prolonged period of time, without systemic toxicity. Thus, in prion-diseased mice, both trazodone and dibenzoylmethane treatment restored memory deficits, abrogated development of neurological signs, prevented neurodegeneration and significantly prolonged survival. In tauopathy-frontotemporal dementia mice, both drugs were neuroprotective, rescued memory deficits and reduced hippocampal atrophy. Further, trazodone reduced p-tau burden. These compounds therefore represent potential new disease-modifying treatments for dementia. Trazodone in particular, a licensed drug, should now be tested in clinical trials in patients.

A Randomized Controlled Trial Comparing the McKenzie Method to Motor Control Exercises in People With Chronic Low Back Pain and a Directional Preference.

Study Design Randomized clinical trial. Background Motor control exercises are believed to improve coordination of the trunk muscles. It is unclear whether increases in trunk muscle thickness can be facilitated by approaches such as the McKenzie method. Furthermore, it is unclear which approach may have superior clinical outcomes. Objectives The primary aim was to compare the effects of the McKenzie method and motor control exercises on trunk muscle recruitment in people with chronic low back pain classified with a directional preference. The secondary aim was to conduct a between-group comparison of outcomes for pain, function, and global perceived effect. Methods Seventy people with chronic low back pain who demonstrated a directional preference using the McKenzie assessment were randomized to receive 12 treatments over 8 weeks with the McKenzie method or with motor control approaches. All outcomes were collected at baseline and at 8-week follow-up by blinded assessors. Results No significant between-group difference was found for trunk muscle thickness of the transversus abdominis (-5.8%; 95% confidence interval [CI]: -15.2%, 3.7%), obliquus internus (-0.7%; 95% CI: -6.6%, 5.2%), and obliquus externus (1.2%; 95% CI: -4.3%, 6.8%). Perceived recovery was slightly superior in the McKenzie group (-0.8; 95% CI: -1.5, -0.1) on a -5 to +5 scale. No significant between-group differences were found for pain or function (P = .99 and P = .26, respectively). Conclusion We found no significant effect of treatment group for trunk muscle thickness. Participants reported a slightly greater sense of perceived recovery with the McKenzie method than with the motor control approach. Level of Evidence Therapy, level 1b-. Registered September 7, 2011 at www.anzctr.org.au (ACTRN12611000971932). J Orthop Sports Phys Ther 2016;46(7):514-522. Epub 12 May 2016. doi:10.2519/jospt.2016.6379.

PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia.

The PERK-eIF2α branch of the Unfolded Protein Response (UPR) mediates the transient shutdown of translation in response to rising levels of misfolded proteins in the endoplasmic reticulum. PERK and eIF2α activation are increasingly recognised in postmortem analyses of patients with neurodegenerative disorders, including Alzheimer's disease, the tauopathies and prion disorders. These are all characterised by the accumulation of misfolded disease-specific proteins in the brain in association with specific patterns of neuronal loss, but the role of UPR activation in their pathogenesis is unclear. In prion-diseased mice, overactivation of PERK-P/eIF2α-P signalling results in the sustained reduction in global protein synthesis, leading to synaptic failure, neuronal loss and clinical disease. Critically, restoring vital neuronal protein synthesis rates by inhibiting the PERK-eIF2α pathway, both genetically and pharmacologically, prevents prion neurodegeneration downstream of misfolded prion protein accumulation. Here we show that PERK-eIF2α-mediated translational failure is a key process leading to neuronal loss in a mouse model of frontotemporal dementia, where the misfolded protein is a form of mutant tau. rTg4510 mice, which overexpress the P301L tau mutation, show dysregulated PERK signalling and sustained repression of protein synthesis by 6 months of age, associated with onset of neurodegeneration. Treatment with the PERK inhibitor, GSK2606414, from this time point in mutant tau-expressing mice restores protein synthesis rates, protecting against further neuronal loss, reducing brain atrophy and abrogating the appearance of clinical signs. Further, we show that PERK-eIF2α activation also contributes to the pathological phosphorylation of tau in rTg4510 mice, and that levels of phospho-tau are lowered by PERK inhibitor treatment, providing a second mechanism of protection. The data support UPR-mediated translational failure as a generic pathogenic mechanism in protein-misfolding disorders, including tauopathies, that can be successfully targeted for prevention of neurodegeneration.

Review: Modulating the unfolded protein response to prevent neurodegeneration and enhance memory.

Recent evidence has placed the unfolded protein response (UPR) at the centre of pathological processes leading to neurodegenerative disease. The translational repression caused by UPR activation starves neurons of the essential proteins they need to function and survive. Restoration of protein synthesis, via genetic or pharmacological means, is neuroprotective in animal models, prolonging survival. This is of great interest due to the observation of UPR activation in the post mortem brains of patients with Alzheimer's, Parkinson's, tauopathies and prion diseases. Protein synthesis is also an essential step in the formation of new memories. Restoring translation in disease or increasing protein synthesis from basal levels has been shown to improve memory in numerous models. As neurodegenerative diseases often present with memory impairments, targeting the UPR to both provide neuroprotection and enhance memory provides an extremely exciting novel therapeutic target.

A randomized controlled trial comparing McKenzie therapy and motor control exercises on the recruitment of trunk muscles in people with chronic low back pain: a trial protocol.

OBJECTIVE: To investigate if McKenzie exercises when applied to a cohort of patients with chronic LBP who have a directional preference demonstrate improved recruitment of the transversus abdominis compared to motor control exercises when measurements were assessed from ultrasound images. DESIGN: A randomized blinded trial with a 12-month follow-up. SETTING: The Physiotherapy department of Concord Hospital a primary health care environment. PARTICIPANTS: 70-adults with greater than three-month history of LBP who have a directional preference. INTERVENTIONS: McKenzie techniques or motor control exercises for 12-sessions over eight weeks. MAIN OUTCOME MEASURES: Transversus abdominus thickness measured from real time ultrasound images, pain, global perceived effect and capacity to self-manage. DISCUSSION: This study will be the first to investigate the possible mechanism of action that McKenzie therapy and motor control exercises have on the recruitment of the transversus abdominus in a cohort of low back pain patients sub-classified with a directional preference. Patients receiving matched exercises according to their directional preference are believed to have better outcomes than those receiving unmatched exercises. A better understanding of the mechanism of action that specific treatments such as motor control exercises or McKenzie exercises have on patients classified with a directional preference will allow therapist to make a more informed choice about treatment options.