A roadmap for affordable genetic medicines.

Nineteen genetic therapies have been approved by the U.S. Food and Drug Administration (FDA) to date, a number that now includes the first CRISPR genome editing therapy for sickle cell disease, CASGEVY (exagamglogene autotemcel). This extraordinary milestone is widely celebrated because of the promise for future genome editing treatments of previously intractable genetic disorders and cancers. At the same time, such genetic therapies are the most expensive drugs on the market, with list prices exceeding $4 million per patient. Although all approved cell and gene therapies trace their origins to academic or government research institutions, reliance on for-profit pharmaceutical companies for subsequent development and commercialization results in prices that prioritize recouping investments, paying for candidate product failures, and meeting investor and shareholder expectations. To increase affordability and access, sustainable discovery-to-market alternatives are needed that address system-wide deficiencies. Here, we present recommendations of a multi-disciplinary task force assembled to chart such a path. We describe a pricing structure that, once implemented, could reduce per-patient cost tenfold and propose a business model that distributes responsibilities while leveraging diverse funding sources. We also outline how academic licensing provisions, manufacturing innovation and supportive regulations can reduce cost and enable broader patient treatment.

The NIH Somatic Cell Genome Editing program.

The move from reading to writing the human genome offers new opportunities to improve human health. The United States National Institutes of Health (NIH) Somatic Cell Genome Editing (SCGE) Consortium aims to accelerate the development of safer and more-effective methods to edit the genomes of disease-relevant somatic cells in patients, even in tissues that are difficult to reach. Here we discuss the consortium's plans to develop and benchmark approaches to induce and measure genome modifications, and to define downstream functional consequences of genome editing within human cells. Central to this effort is a rigorous and innovative approach that requires validation of the technology through third-party testing in small and large animals. New genome editors, delivery technologies and methods for tracking edited cells in vivo, as well as newly developed animal models and human biological systems, will be assembled-along with validated datasets-into an SCGE Toolkit, which will be disseminated widely to the biomedical research community. We visualize this toolkit-and the knowledge generated by its applications-as a means to accelerate the clinical development of new therapies for a wide range of conditions.

Developing a novel dual-injection FDG-PET imaging methodology to study the functional neuroanatomy of gait.

Gait is an excellent indicator of physical, emotional, and mental health. Previous studies have shown that gait impairments in ageing are common, but the neural basis of these impairments are unclear. Existing methodologies are suboptimal and novel paradigms capable of capturing neural activation related to real walking are needed. In this study, we used a hybrid PET/MR system and measured glucose metabolism related to both walking and standing with a dual-injection paradigm in a single study session. For this study, 15 healthy older adults (10 females, age range: 60.5-70.7 years) with normal cognition were recruited from the community. Each participant received an intravenous injection of [18F]-2-fluoro-2-deoxyglucose (FDG) before engaging in two distinct tasks, a static postural control task (standing) and a walking task. After each task, participants were imaged. To discern independent neural functions related to walking compared to standing, we applied a bespoke dose correction to remove the residual 18F signal of the first scan (PETSTAND) from the second scan (PETWALK) and proportional scaling to the global mean, cerebellum, or white matter (WM). Whole-brain differences in walking-elicited neural activity measured with FDG-PET were assessed using a one-sample t-test. In this study, we show that a dual-injection paradigm in healthy older adults is feasible with biologically valid findings. Our results with a dose correction and scaling to the global mean showed that walking, compared to standing, increased glucose consumption in the cuneus (Z = 7.03), the temporal gyrus (Z = 6.91) and the orbital frontal cortex (Z = 6.71). Subcortically, we observed increased glucose metabolism in the supraspinal locomotor network including the thalamus (Z = 6.55), cerebellar vermis and the brainstem (pedunculopontine/mesencephalic locomotor region). Exploratory analyses using proportional scaling to the cerebellum and WM returned similar findings. Here, we have established the feasibility and tolerability of a novel method capable of capturing neural activations related to actual walking and extended previous knowledge including the recruitment of brain regions involved in sensory processing. Our paradigm could be used to explore pathological alterations in various gait disorders.

Safety and tolerability of adjunct non-invasive vagus nerve stimulation in people with parkinson's: a study protocol.

BACKGROUND: Parkinson's disease (PD) is the fastest growing neurological condition worldwide. Recent theories suggest that symptoms of PD may arise due to spread of Lewy-body pathology where the process begins in the gut and propagate transynaptically via the vagus nerve to the central nervous system. In PD, gait impairments are common motor manifestations that are progressive and can appear early in the disease course. As therapies to mitigate gait impairments are limited, novel interventions targeting these and their consequences, i.e., reducing the risk of falls, are urgently needed. Non-invasive vagus nerve stimulation (nVNS) is a neuromodulation technique targeting the vagus nerve. We recently showed in a small pilot trial that a single dose of nVNS improved (decreased) discrete gait variability characteristics in those receiving active stimulation relative to those receiving sham stimulation. Further multi-dose, multi-session studies are needed to assess the safety and tolerability of the stimulation and if improvement in gait is sustained over time. DESIGN: This will be an investigator-initiated, single-site, proof-of-concept, double-blind sham-controlled randomised pilot trial in 40 people with PD. Participants will be randomly assigned on a 1:1 ratio to receive either active or sham transcutaneous cervical VNS. All participants will undergo comprehensive cognitive, autonomic and gait assessments during three sessions over 24 weeks, in addition to remote monitoring of ambulatory activity and falls, and exploratory analyses of cholinergic peripheral plasma markers. The primary outcome measure is the safety and tolerability of multi-dose nVNS in PD. Secondary outcomes include improvements in gait, cognition and autonomic function that will be summarised using descriptive statistics. DISCUSSION: This study will report on the proportion of eligible and enrolled patients, rates of eligibility and reasons for ineligibility. Adverse events will be recorded informing on the safety and device tolerability in PD. This study will additionally provide us with information for sample size calculations for future studies and evidence whether improvement in gait control is enhanced when nVNS is delivered repeatedly and sustained over time. TRIAL REGISTRATION: This trial is prospectively registered at www.isrctn.com/ISRCTN19394828 . Registered August 23, 2021.

Dicer-TRBP complex formation ensures accurate mammalian microRNA biogenesis.

RNA-mediated gene silencing in human cells requires the accurate generation of ∼22 nt microRNAs (miRNAs) from double-stranded RNA substrates by the endonuclease Dicer. Although the phylogenetically conserved RNA-binding proteins TRBP and PACT are known to contribute to this process, their mode of Dicer binding and their genome-wide effects on miRNA processing have not been determined. We solved the crystal structure of the human Dicer-TRBP interface, revealing the structural basis of the interaction. Interface residues conserved between TRBP and PACT show that the proteins bind to Dicer in a similar manner and by mutual exclusion. Based on the structure, a catalytically active Dicer that cannot bind TRBP or PACT was designed and introduced into Dicer-deficient mammalian cells, revealing selective defects in guide strand selection. These results demonstrate the role of Dicer-associated RNA binding proteins in maintenance of gene silencing fidelity.

The long-term impacts of opioid use before and after joint arthroplasty: matched cohort analysis of New Zealand linked register data.

BACKGROUND: Opioids are commonly used both before and after total joint arthroplasty (TJA). OBJECTIVE: The objective of this study was to estimate the long-term effects of pre- and perioperative opioid use in patients undergoing TJA. METHODS: We used linked population datasets to identify all (n =18,666) patients who had a publicly funded TJA in New Zealand between 2011 and 2013. We used propensity score matching to match individuals who used opioids either before surgery, during hospital stay, or immediately post-discharge with individuals who did not based on a comprehensive set of covariates. Regression analysis was used to estimate the effect of opioid use on health and socio-economic outcomes over 5 years. RESULTS: Opioid use in the 3 months prior to surgery was associated with significant increases in healthcare utilization and costs (number of hospitalizations 6%, days spent in hospital 14.4%, opioid scripts dispensed 181%, and total healthcare costs 11%). Also increased were the rate of receiving social benefits (2 percentage points) and the rates of opioid overdose (0.5 percentage points) and mortality (3 percentage points). Opioid use during hospital stay or post-discharge was associated with increased long-term opioid use, but there was little evidence of other adverse effects. CONCLUSIONS: Opioid use before TJA is associated with significant negative health and economic consequences and should be limited. This has implications for opioid prescribing in primary care. There is little evidence that peri- or post-operative opioid use is associated with significant long-term detriments.

Opioids are commonly used both before and after total joint replacement surgery to manage pain in patients with osteoarthritis. This study investigates the long-term consequences of opioid use around total joint replacement surgery in New Zealand during 2011­2013 using administrative data. We compare the outcomes of surgery patients who used opioids (treatment group) to those who did not (control group) but who had very similar pre-surgery characteristics as the treatment cohort. We find that opioid use in the months prior to surgery was associated with significant increases in healthcare utilization and costs, higher likelihood of receiving social benefits, and higher risk of opioid overdose and mortality 5 years post-surgery. Opioid use during hospital stay or post-discharge was associated with increased long-term opioid use, but there was little evidence of other adverse effects. These results highlight the importance of ongoing efforts to reduce opioid use before surgery.

Epidemiology of cruciate ligament injuries in New Zealand: exploring differences by ethnicity and socioeconomic status.

OBJECTIVES: To investigate the temporal trends and ethnic and socioeconomic disparities in cruciate ligament (CL) injury incidence and associated costs in New Zealand over a 14-year period. METHODS: All CL injury claims lodged between 2007 and 2020 were extracted from the Accident Compensation Corporation (a nationwide no-fault injury compensation scheme) claims dataset. Age-adjusted and sex-adjusted incidence rates, total injury costs and costs per claim were calculated for each year for total population and subgroups. RESULTS: The total number of CL injury claims increased from 6972 in 2007 to 8304 in 2019, then decreased to 7068 in 2020 (likely due to widespread COVID-19 restrictions; analysis is therefore restricted to 2007-2019 hereafter). The (age-adjusted and sex-adjusted) incidence rate remained largely unchanged and was 173 cases per 100 000 people in 2019. There was a 127% increase in total injury claims costs and a 90% increase in costs per claim. Pacific people had the highest incidence rate and costs per 100 000 people, while Asians had the lowest; European, Maori and 'other' ethnicities had similar incidence rates and total costs. Incidence rates and total costs increased with income and decreased with neighbourhood deprivation. Costs per claim differed little by ethnicity, but increased with income level. CONCLUSION: The number and costs of CL injury claims in New Zealand are increasing. There are ethnic and socioeconomic disparities in CL incidence rates and costs, which are important to address when designing CL injury prevention programmes and programmes aimed at improving equity of access to medical care.

Are the outcomes of relative motion extension orthoses non-inferior and cost-effective compared with dynamic extension orthoses for management of zones V-VI finger extensor tendon repairs: A randomized controlled trial.

INTRODUCTION: There is no comparative evidence for relative motion extension (RME) orthosis with dynamic wrist-hand-finger-orthosis (WHFO) management of zones V-VI extensor tendon repairs. PURPOSE OF THE STUDY: To determine if RME with wrist-hand-orthosis (RME plus) is noninferior to dynamic WHFO for these zones in clinical outcomes. STUDY DESIGN: Randomized controlled non-inferiority trial. METHODS: Skilled hand therapists managed 37 participants (95% male; mean age 39 years, SD 18) with repaired zones V-VI extensor tendons randomized to RME plus (n = 19) or dynamic WHFO (n = 18). The primary outcome of percentage of total active motion (%TAM) and secondary outcomes of satisfaction, function, and quality of life were measured at week-6 and -12 postoperatively; percentage grip strength (%Grip), complication rates, and cost data at week-12. Following the intention-to-treat principle non-inferiority was assessed using linear regression analysis (5% significance) and adjusted for injury complexity factors with an analysis of costs performed. RESULTS: RME plus was noninferior for %TAM at week-6 (adjusted estimates 2.5; 95% CI -9.0 to 14.0), %TAM at week-12 (0.3; -6.8 to 7.5), therapy satisfaction at week-6 and -12, and orthosis satisfaction, QuickDASH, and %Grip at week-12. Per protocol analysis yielded 2 tendon ruptures in the RME plus orthoses and 1 in the dynamic WHFO. There were no differences in health system and societal cost, or quality-adjusted life years. DISCUSSION: RME plus orthosis wearers had greater injury complexity than those in dynamic WHFOs, with overall rupture rate for both groups comparatively more than reported by others; however, percentage %TAM was comparable. The number of participants needed was underestimated, so risk of chance findings should be considered. CONCLUSIONS: RME plus management of finger zones V-VI extensor tendon repairs is non-inferior to dynamic WHFO in %TAM, therapy and orthotic satisfaction, QuickDASH, and %Grip. Major costs associated with this injury are related to lost work time.

Prioritizing Healthcare Interventions: A Comparison of Multicriteria Decision Analysis and Cost-Effectiveness Analysis.

OBJECTIVES: To investigate the extent to which stated preferences for treatment criteria elicited using multicriteria decision analysis (MCDA) methods are consistent with the trade-offs (implicitly) applied in cost-effectiveness analysis (CEA), and the impact of any differences on the prioritization of treatments. METHODS: We used existing MCDA and CEA models developed to evaluate interventions for knee osteoarthritis in the New Zealand population. We established equivalent input parameters for each model, for the criteria "treatment effectiveness," "cost," "risk of serious harms," and "risk of mild-to-moderate harms" across a comprehensive range of (hypothetical) interventions to produce a complete ranking of interventions from each model. We evaluated the consistency of these rankings between the 2 models and investigated any systematic differences between the (implied) weight placed on each criterion in determining rankings. RESULTS: There was an overall moderate-to-strong correlation in intervention rankings between the MCDA and CEA models (Spearman correlation coefficient = 0.51). Nevertheless, there were systematic differences in the evaluation of trade-offs between intervention attributes and the resulting weights placed on each criterion. The CEA model placed lower weights on risks of harm and much greater weight on cost (at all accepted levels of willingness-to-pay per quality-adjusted life-year than did respondents to the MCDA survey. CONCLUSIONS: MCDA and CEA approaches to inform intervention prioritization may give systematically different results, even when considering the same criteria and input data. These differences should be considered when designing and interpreting such studies to inform treatment prioritization decisions.

Total Hip and Knee Arthroplasties Are Highly Cost-Effective Procedures: The Importance of Duration of Follow-Up.

BACKGROUND: Total hip and knee arthroplasties (THA/TKA) are clinically effective but high cost procedures. The aim of this study is to perform a cost-effectiveness analysis of THA and TKA in the New Zealand (NZ) healthcare system. METHODS: Data were collected from 713 patients undergoing THA and 520 patients undergoing TKA at our local public hospital. SF-6D utility values were obtained from participants preoperatively and 1-year postoperatively, and deaths and any revision surgeries from patient records and the New Zealand Joint Registry at minimum 8-year follow-up. A continuous-time state-transition simulation model was used to estimate costs and health gains to 15 years. Quality-adjusted life years (QALYs), treatment costs, and incremental cost-effectiveness ratios (ICERs) were calculated to determine cost effectiveness. ICERs below NZ gross domestic product (GDP; NZ$60 600) and 0.5 times GDP per capita were considered "cost effective" and "highly cost effective" respectively. RESULTS: Cumulative health gains were 2.8 QALYs (THA) and 2.3 QALYs (TKA) over 15 years. Cost effectiveness improved from ICERs of NZ$74,400 (THA) and NZ$93,000 (TKA) at 1 year to NZ$6000 (THA) and NZ$7500 (TKA) at 15 years. THA and TKA were cost effective after 2 years and highly cost effective after 3 years. QALY gains and cost effectiveness were greater in patients with worse preoperative functional status and younger age. CONCLUSION: THA and TKA are highly cost-effective procedures over longer term horizons. Although preoperative status and age were associated with cost effectiveness, both THA and TKA remained cost effective in patients with less severe preoperative scores and older ages.

Interprofessional education in the rural environment to enhance multidisciplinary care in future practice: Breaking down silos in tertiary health education.

OBJECTIVE: Western Sydney University has implemented a rural interprofessional learning programme to promote collaborative care approaches to enhance cross-discipline communications, improve knowledge and clarity of roles and improve patient care and outcomes. DESIGN: Rural interprofessinal learning is an interprofessional educational approach, consisting of simulations of complex health events. Simulation methodology frames the study with a focus on human interaction. A mixed-methods evaluation has been conducted, incorporating pre- and post- event participant surveys along with semi-structured focus groups. SETTING: Simulations are conducted in the rural setting, including community settings, working farms and rural hospitals. MAIN OUTCOME MEASURES: Reflexive thematic analysis was used to identify themes measuring students' perceptions of interdisciplinary care, knowlede of other health discipline roles and skills and how they believe the exercise will influence their future practice. Facilitator feedback regarding the efficacy of the simulations was also recorded and analysed using reflexive thematic analysis. PARTICIPANTS: Care of simulated patient(s)/bystander(s) is primarily provided by paramedicine, nursing and medical students; however, increasing interest has expanded the programme to include students from a range of allied health professions. Simulations are facilitated by a multidisciplinary team of experienced practitioners and specialists. INTERVENTION: Four rural interprofessional learning events have been held. RESULTS: 120 students have participated in the evaluation. Findings include increased understanding of the contributions of other disciplines in enhancing patient care, team approaches, cross-discipline communication and a need to engage in collaborative care in future practice. CONCLUSION: Creating a collaborative learning environment creates a culture of multidisciplinary care, enhancing patient care and improving outcomes. The rural interprofessional learning model is an effective interprofessional educational approach, which can be repeated, refined and improved for continual professional development.

Two Spatially Distinct Posterior Alpha Sources Fulfill Different Functional Roles in Attention.

Directing attention helps to extract relevant information and suppress distracters. Alpha brain oscillations (8-12 Hz) are crucial for this process, with power decreases facilitating processing of important information and power increases inhibiting brain regions processing irrelevant information. Evidence for this phenomenon arises from visual attention studies (Worden et al., 2000); however, the effect also exists in other modalities, including the somatosensory system (Haegens et al., 2011) and intersensory attention tasks (Foxe and Snyder, 2011). We investigated in human participants (10 females, 10 males) the role of alpha oscillations in focused (0/100%) versus divided (40/60%) attention, both across modalities (visual/somatosensory; Experiment 1) and within the same modality (visual domain: across hemifields; Experiment 2) while recording EEG over 128 scalp electrodes. In Experiment 1, participants divided their attention between visual and somatosensory modality to determine the temporal/spatial frequency of a target stimulus (vibrotactile stimulus/Gabor grating). In Experiment 2, participants divided attention between two visual hemifields to identify the orientation of a Gabor grating. In both experiments, prestimulus alpha power in visual areas decreased linearly with increasing attention to visual stimuli. In contrast, prestimulus alpha power in parietal areas was lower when attention was divided between modalities/hemifields compared with focused attention. These results suggest there are two alpha sources, one of which reflects the "visual spotlight of attention" and the other reflects attentional effort. To our knowledge, this is the first study to show that attention recruits two spatially distinct alpha sources in occipital and parietal brain regions, acting simultaneously but serving different functions in attention.SIGNIFICANCE STATEMENT Attention to one spatial location/sensory modality leads to power changes of alpha oscillations (∼10 Hz) with decreased power over regions processing relevant information and power increases to actively inhibit areas processing "to-be-ignored" information. Here, we used detailed source modeling to investigate EEG data recorded during separate unimodal (visual) and multimodal (visual and somatosensory) attention tasks. Participants either focused their attention on one modality/spatial location or directed it to both. We show for the first time two distinct alpha sources are active simultaneously but play different roles. A sensory (visual) alpha source was linearly modulated by attention representing the "visual spotlight of attention." By contrast, a parietal alpha source was modulated by attentional effort, showing lowest alpha power when attention was divided.

Spatially congruent negative BOLD responses to different stimuli do not summate in visual cortex.

The negative BOLD response (NBR) is a prevalent feature of brain activity during sensory and cognitive tasks. It is thought to reflect suppression or deactivation of cortical areas unrequired for task performance, but much remains to be understood regarding its response properties and generative pathways. Here we study a unique property of sensory cortex NBR that most distinguishes it from positive BOLD responses (PBR), its appearance in a single location due to different stimuli. We investigate whether such NBR are additive, as a means of studying whether stimulus driven NBR arise via a single or multiple pathways. During fMRI, subject's passively viewed separate checkerboard stimulation of the foveal and middle-eccentricity areas of the left visual field and a third condition that stimulated both areas concurrently. PBR was observed in the contralateral primary visual cortex and NBR was seen throughout the ipsilateral cortex as well as in contralateral regions superior and anterior to the PBR. Strong spatial overlap of NBRs to all three conditions was observed. We found that neither PBR nor NBR were additive. NBR amplitudes to combined stimuli were equal to those of the strongest (foveal) stimulus alone, despite the mid-eccentricity stimulus inducing substantial NBR on its own. The lack of summation of NBRs, both in the same and opposite hemispheres to the PBR, suggests that they arise from a single pathway. Our findings suggest that although individual stimuli each exert a separate inhibitory effect on non-stimulated regions, once in combination these effects operate as a binary system. Deactivation of a given visual area is driven by a single signal, representing only the largest of the contributing sources.

Opioid Use and Total Joint Replacement.

PURPOSE OF REVIEW: We provide an overview of recent research into the relationship between preoperative opioid use and total joint replacement outcomes. RECENT FINDINGS: Recent findings indicate that total joint replacement patients with a history of preoperative opioid use experience higher rates of infection, revision, short-term complications, and prolonged postoperative opioid use, along with fewer improvements in pain and function following surgery. These risks are particularly pronounced among chronic opioid users. While the baseline risk profiles of these patients may contribute to higher rates of adverse outcomes, it is also plausible that certain outcomes are directly impacted by opioid use through mechanisms such as opioid-induced hyperalgesia and immunosuppression. There is little available data on the efficacy of interventions that aim to mitigate these risks. Well-designed clinical trials are needed to evaluate the efficacy of targeted perioperative interventions that aim to improve outcomes for this high-risk surgical population. Where such trials are not feasible, additional high-quality observational studies are necessary to further our understanding of the mechanisms underlying the relationships between opioid use and specific adverse outcomes.

The Functional Outcomes of Patients With Knee Osteoarthritis Managed Nonoperatively at the Joint Clinic at 5-Year Follow-Up: Does Surgical Avoidance Mean Success?

BACKGROUND: Nonoperative management of patients with knee osteoarthritis (OA) through multidisciplinary programs may delay or reduce the need for total knee arthroplasty (TKA). However, avoidance of surgery may not represent success for the patient. METHODS: A cohort of 120 patients with knee OA managed with at least 6 months of supervised nonoperative treatment coordinated through the Joint Clinic were reviewed at 5 years. Outcomes including Oxford knee score (OKS), Short Form 12 (SF-12), and SF-6D and other measures including analgesia use, global change, and perception of need for surgery were collected and compared with those from the cohort who had undergone TKA. RESULTS: Seventy (62.5%) surviving patients were still being managed nonoperatively. There was no significant change in any outcome score (OKS, SF-12 physical component score, SF-12 mental component score, SF-6D) (P = .26 to .84). Forty-two patients had undergone TKA with mean time to surgery 29.0 months (range, 9-69 months). In this group, the mean OKS fell from 17.9 at baseline to 10.3 (range, 3-21) preoperatively (P < .0001) and at 5 years there was a significant improvement from baseline in OKS, SF-12 physical component score, and SF-6D scores (P < .0001). All outcome scores and change in scores were significantly higher for the surgical group (all P < .001). CONCLUSION: Although a high proportion of patients with knee OA have avoided surgery at 5 years, their outcomes show no improvement from baseline and are poorer than those who have undergone TKA. Avoidance of surgery should not necessarily be regarded as an indicator of success of nonoperative treatment for the patient.

Risk Factors for Chronic Opioid Use Following Hip and Knee Arthroplasty: Evidence from New Zealand Population Data.

BACKGROUND: Patients awaiting total joint arthroplasty (TJA) have high rates of opioid use, and many continue to use opioid medications long term after surgery. The objective of this study is to estimate the risk factors associated with chronic opioid use after TJA in a comprehensive population-based cohort. METHODS: All patients undergoing TJA in the New Zealand public healthcare system were identified from Ministry of Health records. Dispensing of opioid medications up to 3 years postsurgery and potential risk factors, including demographic, socioeconomic, and surgery-related characteristics, pre-existing medical comorbidities, and use of other analgesic medications prior to surgery, were identified from linked population databases. Logistic regression analysis was used to identify factors associated with chronic postoperative opioid use. RESULTS: The strongest risk factor for chronic postoperative opioid use was preoperative opioid use. Other significant risk factors included perioperative opioid use, history of alcohol or drug abuse, younger age, female gender, knee arthroplasty, several comorbid health conditions, and preoperative use of some analgesic medications. Protective factors included higher education levels and preoperative use of nonsteroidal anti-inflammatory drugs. Most risk factors had similar effects on chronic postoperative opioid use irrespective of the length of follow-up considered (1, 2, or 3 years). CONCLUSION: This study of a comprehensive nationwide population-based cohort of TJA patients with 3 years of follow-up identified several modifiable risk factors and other easily measured patient characteristics associated with higher risk of long-term postoperative opioid use.

The Outcomes of Nonoperative Management of Patients With Hip and Knee Osteoarthritis Triaged to a Physiotherapy-Led Clinic at Minimum 5-Year Follow-Up and Factors Associated With Progression to Surgery.

BACKGROUND: The purpose of this study is to determine outcomes of a nonoperative treatment service for hip and knee osteoarthritis (OA), the "Joint Clinic," at minimum 5-year follow-up, and investigate factors that may influence progression to joint replacement surgery. METHODS: This is an observational cohort study of 337 patients with hip (n = 151, 45%) or knee OA (n = 186, 55%) seen at the Joint Clinic, at 5-7 years of follow-up. Kaplan-Meier survival curves were used to determine survivorship of the affected joint and Cox regression used to determine factors associated with time to surgery. RESULTS: At mean 6-year follow up, 188 (56%) patients had undergone or were awaiting total joint arthroplasty, 127 (38%) were still being managed nonoperatively, and 22 (7%) had died without having surgery. Patients with hip OA were more likely to have required surgery (111/151, 74%) than patients with knee OA (77/186, 41%) (chi-square = 33.6, P < .001). The 7-year surgery-free survival for hip OA was 23.7% and knee OA 55.9% (P < .001). Factors associated with increased likelihood of surgery were joint affected (hip, hazard ratio [HR] 2.80), Kellgren-Lawrence (KL) grade (KL 3, HR 2.02; KL 4, 4.79), and Oxford Hip/Knee Score (HR 1.34 for each 5 points worse at baseline). CONCLUSION: More than 50% of the patients referred to secondary care with mild-moderate knee OA may not need surgery at 7 years. Patients with hip OA and those with severe radiographic changes are more likely to require surgery and should not be delayed if there is not an adequate response to conservative measures.

The relationship between negative BOLD responses and ERS and ERD of alpha/beta oscillations in visual and motor cortex.

Previous work has investigated the electrophysiological origins of the intra-modal (within the stimulated sensory cortex) negative BOLD fMRI response (NBR, decrease from baseline) but little attention has been paid to the origin of cross-modal NBRs, those in a different sensory cortex. In the current study we use simultaneous EEG-fMRI recordings to assess the neural correlates of both intra- and cross-modal responses to left-hemifield visual stimuli and right-hand motor tasks, and evaluate the balance of activation and deactivation between the visual and motor systems. Within- and between-subject covariations of EEG and fMRI responses to both tasks are assessed to determine how patterns of event-related desynchronization/synchronisation (ERD/ERS) of alpha/beta frequency oscillations relate to the NBR in the two sensory cortices. We show that both visual and motor tasks induce intra-modal NBR and cross-modal NBR (e.g. visual stimuli evoked NBRs in both visual and motor cortices). In the EEG data, bilateral intra-modal alpha/beta ERD were consistently observed to both tasks, whilst the cross-modal EEG response varied across subjects between alpha/beta ERD and ERS. Both the mean cross-modal EEG and fMRI response amplitudes showed a small increase in magnitude with increasing task intensity. In response to the visual stimuli, subjects displaying cross-modal ERS of motor beta power displayed a significantly larger magnitude of cross-modal NBR in motor cortex. However, in contrast to the motor stimuli, larger cross-modal ERD of visual alpha power was associated with larger cross-modal visual NBR. Single-trial correlation analysis provided further evidence of relationship between EEG signals and the NBR, motor cortex beta responses to motor tasks were significantly negatively correlated with cross-modal visual cortex NBR amplitude, and positively correlated with intra-modal motor cortex PBR. This study provides a new body of evidence that the coupling between BOLD and low-frequency (alpha/beta) sensory cortex EEG responses extends to cross-modal NBR.

The Fear Reduction Exercised Early (FREE) approach to management of low back pain in general practice: A pragmatic cluster-randomised controlled trial.

BACKGROUND: Effective and cost-effective primary care treatments for low back pain (LBP) are required to reduce the burden of the world's most disabling condition. This study aimed to compare the clinical effectiveness and cost-effectiveness of the Fear Reduction Exercised Early (FREE) approach to LBP (intervention) with usual general practitioner (GP) care (control). METHODS AND FINDINGS: This pragmatic, cluster-randomised controlled trial with process evaluation and parallel economic evaluation was conducted in the Hutt Valley, New Zealand. Eight general practices were randomly assigned (stratified by practice size) with a 1:1 ratio to intervention (4 practices; 34 GPs) or control group (4 practices; 29 GPs). Adults presenting to these GPs with LBP as their primary complaint were recruited. GPs in the intervention practices were trained in the FREE approach, and patients presenting to these practices received care based on the FREE approach. The FREE approach restructures LBP consultations to prioritise early identification and management of barriers to recovery. GPs in control practices did not receive specific training for this study, and patients presenting to these practices received usual care. Between 23 September 2016 and 31 July 2017, 140 eligible patients presented to intervention practices (126 enrolled) and 110 eligible patients presented to control practices (100 enrolled). Patient mean age was 46.1 years (SD 14.4), and 46% were female. The duration of LBP was less than 6 weeks in 88% of patients. Primary outcome was change from baseline in patient participant Roland Morris Disability Questionnaire (RMDQ) score at 6 months. Secondary patient outcomes included pain, satisfaction, and psychosocial indices. GP outcomes included attitudes, knowledge, confidence, and GP LBP management behaviour. There was active and passive surveillance of potential harms. Patients and outcome assessors were blind to group assignment. Analysis followed intention-to-treat principles. A total of 122 (97%) patients from 32 GPs in the intervention group and 99 (99%) patients from 25 GPs in the control group were included in the primary outcome analysis. At 6 months, the groups did not significantly differ on the primary outcome (adjusted mean RMDQ score difference 0.57, 95% CI -0.64 to 1.78; p = 0.354) or secondary patient outcomes. The RMDQ difference met the predefined criterion to indicate noninferiority. One control group participant experienced an activity-related gluteal tear, with no other adverse events recorded. Intervention group GPs had improvements in attitudes, knowledge, and confidence compared with control group GPs. Intervention group GP LBP management behaviour became more guideline concordant than the control group. In cost-effectiveness, the intervention dominated control with lower costs and higher Quality-Adjusted Life Year (QALY) gains. Limitations of this study were that although adequately powered for primary outcome assessment, the study was not powered for evaluating some employment, healthcare use, and economic outcomes. It was also not possible for research nurses (responsible for patient recruitment) to be masked on group allocation for practices. CONCLUSIONS: Findings from this study suggest that the FREE approach improves GP concordance with LBP guideline recommendations but does not improve patient recovery outcomes compared with usual care. The FREE approach may reduce unnecessary healthcare use and produce economic benefits. Work participation or health resource use should be considered for primary outcome assessment in future trials of undifferentiated LBP. TRIAL REGISTRATION: ACTRN12616000888460.

Clinical applications of CRISPR-based genome editing and diagnostics.

Clustered regularly interspaced short palindromic repeats (CRISPR)-driven genome editing has rapidly transformed preclinical biomedical research by eliminating the underlying genetic basis of many diseases in model systems and facilitating the study of disease etiology. Translation to the clinic is under way, with announced or impending clinical trials utilizing ex vivo strategies for anticancer immunotherapy or correction of hemoglobinopathies. These exciting applications represent just a fraction of what is theoretically possible for this emerging technology, but many technical hurdles must be overcome before CRISPR-based genome editing technology can reach its full potential. One exciting recent development is the use of CRISPR systems for diagnostic detection of genetic sequences associated with pathogens or cancer. We review the biologic origins and functional mechanism of CRISPR systems and highlight several current and future clinical applications of genome editing.