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Objective: Redundant nerve roots (RNRs) seen in conjunction with lumbar spinal stenosis (LSS) are well-described radiographic findings. Several studies suggest their presence may be a negative prognostic indicator of postoperative outcome. Our hypothesis was that severe RNR (informally known as the spaghetti sign [SS]) can serve as a reliable marker of LSS that would benefit from surgical decompression. We sought to evaluate a grading scale for RNR, characterize the association with stenosis, and investigate the clinical implications of RNR., Methods: We conducted a retrospective chart review of 72 patients who underwent lumbar spine surgery from 2016 to 2018 at 1 institution. Preoperative T2 magnetic resonance imaging scans were graded by 3 reviewers for severity of stenosis (0-4), severity of RNR (0-3), and rostral versus caudal RNR. SS was defined as RNR score ≥2 (clear-cut or marked nerve root irregularity). Preoperative and postoperative Oswestry Disability Index scores were analyzed by stenosis and RNR severity., Results: Seventy-one (98%) patients had severe stenosis (score ≥3) and 25 (35%) had a SS. SS was 100% specific for high-grade stenosis. If patients had a SS, it was more likely rostral (P=0.02). Postoperative Oswestry Disability Index scores improved significantly, but there were no differences related to RNR score, presence of SS, or stenosis severity., Conclusions: The study demonstrated that there is a significant association between SS and severe LSS and that presence of RNR is not a negative prognostic indicator for postoperative outcomes., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Deep brain stimulation (DBS) targeting the globus pallidus interna (GPi) has been shown to significantly improve motor symptoms for the treatment of medication-refractory Parkinson's disease. Yet, heterogeneity in clinical outcomes persists, possibly due to suboptimal target identification within the GPi. By leveraging robust sampling of the GPi and 6-month postsurgical outcomes, this study aims to determine optimal symptom-specific GPi DBS targets., Methods: In this study, the authors analyzed the anatomical lead location and 6-month postsurgical, double-blinded outcome measures of 86 patients who underwent bilateral GPi DBS. These patients were selected from the multicenter Veterans Affairs (VA)/National Institutes of Neurological Disorders and Stroke (NINDS) Cooperative Studies Program (CSP) 468 study to identify the optimal target zones ("sweet spots") for the control of overall motor (United Parkinson's Disease Rating Scale [UPDRS]-III), axial, tremor, rigidity, and bradykinesia symptoms. Lead coordinates were normalized to Montreal Neurological Institute space and the optimal target zones were identified and validated using a leave-one-patient-out approach., Results: The authors' findings revealed statistically significant optimal target zones for UPDRS-III (R = 0.37, p < 0.001), axial (R = 0.22, p = 0.042), rigidity (R = 0.20, p = 0.021), and bradykinesia (R = 0.23, p = 0.004) symptoms. These zones were localized within the primary motor and premotor subdivisions of the GPi. Interestingly, these zones extended beyond the GPi lateral border into the GPi-globus pallidus externa (GPe) lamina and into the GPe, but they did not reach the GPi ventral border, challenging traditional surgical approaches based on pallidotomies., Conclusions: Drawing upon a robust dataset, this research effectively delineates specific optimal target zones for not only overall motor improvement but also symptom subscores. These insights hold the potential to enhance the precision of targeting in subsequent bilateral GPi DBS surgical procedures.

Objective: Neurosurgery is among the most demanding and time-consuming occupations, and with diversity and inclusion initiatives only recently increasing the number of women in the field, efforts still need to be made to help neurosurgery become more accommodating for pregnancy and child-rearing. Thus, the present study sought to be the first to investigate this issue through in-depth qualitative interviews of women in neurosurgery., Methods: A total of 33 female neurosurgeons participated in semistructured Zoom interviews. Cocoding and thematic analysis were conducted with interview transcripts to determine themes and corresponding subthemes with regard to these women's experiences with pregnancy and child-rearing, advice for future mothers in neurosurgery, and suggestions for improving the field of neurosurgery for those desiring children., Results: Among the 33 participants, 22 (66.7%) had given birth to or adopted at least one child, had at least one stepchild, or were pregnant at the time of the interview. Three themes emerged regarding these 22 women's experiences with pregnancy and child-rearing: 1) challenges with the physiological changes of pregnancy, 2) feelings of guilt and anxiety, and 3) reliance on loved ones for childcare. Three themes emerged among these 22 women's advice for future mothers in neurosurgery: 1) set realistic expectations, 2) take control of your schedule, and 3) realize that there is no "right" time to start a family. Finally, two themes emerged among all 33 participants' suggestions for making neurosurgery more feasible for pregnancy and child-rearing: 1) revamping of on-site resources, and 2) improved guidance on family planning, childbearing, and maternity leave. The most prominent subtheme in the authors' study was a call for improved on-site daycare under the "revamping of on-site resources" theme, with a particular emphasis on 24/7 operation., Conclusions: The authors' data have illustrated the themes of the experiences and thoughts of women in a field where pregnancy and child-rearing are arguably the most challenging of any occupation. Resources such as improved on-site daycare and organized, program-specific information sets for future mothers appear to comprise a consensus of suggested solutions by the women directly experiencing these challenges. The authors' results may be useful in guiding system-wide changes that may improve the field of neurosurgery for current and future mothers.

Background: Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive alternative to surgical resection for drug-resistant mesial temporal lobe epilepsy (mTLE). Reported rates of seizure freedom are variable and long-term durability is largely unproven. Anterior temporal lobectomy (ATL) remains an option for patients with MRgLITT treatment failure. However, the safety and efficacy of this staged strategy is unknown., Methods: This multicentre, retrospective cohort study included 268 patients consecutively treated with mesial temporal MRgLITT at 11 centres between 2012 and 2018. Seizure outcomes and complications of MRgLITT and any subsequent surgery are reported. Predictive value of preoperative variables for seizure outcome was assessed., Results: Engel I seizure freedom was achieved in 55.8% (149/267) at 1 year, 52.5% (126/240) at 2 years and 49.3% (132/268) at the last follow-up ≥1 year (median 47 months). Engel I or II outcomes were achieved in 74.2% (198/267) at 1 year, 75.0% (180/240) at 2 years and 66.0% (177/268) at the last follow-up. Preoperative focal to bilateral tonic-clonic seizures were independently associated with seizure recurrence. Among patients with seizure recurrence, 14/21 (66.7%) became seizure-free after subsequent ATL and 5/10 (50%) after repeat MRgLITT at last follow-up≥1 year., Conclusions: MRgLITT is a viable treatment with durable outcomes for patients with drug-resistant mTLE evaluated at a comprehensive epilepsy centre. Although seizure freedom rates were lower than reported with ATL, this series represents the early experience of each centre and a heterogeneous cohort. ATL remains a safe and effective treatment for well-selected patients who fail MRgLITT., Competing Interests: Competing interests: Several centres that contributed data to this study are sites in the ongoing Stereotactic Laser Ablation for Temporal Lobe Epilepsy (SLATE) study (NCT02844465) sponsored by Medtronic (Minneapolis, Minnesota, USA). Procedures reported here precede any enrolment in SLATE. This study was not industry sponsored. AS is Chief Medical Officer of Medtronic Neuromodulation Operating Unit., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective and Importance: With an aging population and increasing utilization of both cochlear implants (CI) to treat hearing loss and deep brain stimulation (DBS) to treat neurodegenerative movement disorders, more patients will be sequentially implanted with the two devices. As such, understanding both presurgical evaluations and surgical procedures will be of great importance to the treating cochlear implant surgeon and neurosurgeon in optimizing outcomes for both conditions., Clinical Presentation: Two illustrative cases of sequential CI followed by DBS are reviewed. Relevant pre-, intra-, and postoperative issues are discussed for both DBS following CI surgery and CI following DBS surgery., Conclusion: Despite the potential for challenges, sequential CI and DBS (and vice versa) can provide substantial benefit to those individuals with severe hearing loss and movement disorders. A thorough understanding of both devices is critical to ensuring optimal outcomes.

Objectives: Deep brain stimulation (DBS) has become an established neuromodulation therapy; however, surgical site complications such as hardware skin erosion remain an important risk and can predispose to infection, requiring explantation of the system. Nuances of surgical technique can affect wound healing, cosmetic outcome, comfort, and risk of infection. In this study, we describe our experience with a layered closure technique using a vascularized pericranial flap for improving cosmesis and protection of the implanted hardware against skin erosion and infection., Materials and Methods: We retrospectively reviewed 636 individuals (746 lead implantations) who underwent DBS surgery by a single academic neurosurgeon between 2001 and 2020. A layered pericranial flap closure technique for the burr-hole and connector sites was instituted in 2015. We assessed the effects of a multimodal infection prevention approach that included the pericranial flap on hardware complication rates compared with the premultimodality cohort, and we report the nuances of the technique., Results: In our institutional experience, we found that implementation of a pericranial flap closure technique can enhance the subjective cosmetic result at the burr-hole cover site and increase patient comfort and satisfaction. In addition, we found a decrease in hardware infection rates in the current cohort with a multimodal infection prevention regimen that includes the pericranial-flap technique (n = 256, 2015-2020 period) to 1.2% (p = 0.006), from 6.9% in the earlier cohort (n = 490, 2001-2015 period)., Conclusions: The report highlights the potential of a pericranial-flap closure technique as a surgical adjunct to improve DBS surgical site healing and cosmesis and may, as part of a multimodal strategy, contribute to decreased risk of skin breakdown and hardware infection., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Primary Objective: While repetitive transcranial magnetic stimulation (rTMS) has shown efficacy for cognitive difficulties accompanying depression, it is unknown if it can improve cognition in persons with traumatic brain injury., Research Design: Using a sham-controlled crossover design, we tested the capacity of high frequency rTMS of the prefrontal cortex to improve neuropsychological performance in attention, learning and memory, and executive function., Methods: Twenty-six participants with cognitive complaints and a history of mild-to-moderate traumatic brain injury were randomly assigned to receive first either active or sham 10 Hz stimulation for 20 minutes (1200 pulses) per session for five consecutive days. After a one-week washout, the other condition (active or sham) was applied. Pre- and post-treatment measures included neuropsychological tests, cognitive and emotional symptoms, and EEG., Main Outcomes and Results: Results indicated no effect of treatment on cognitive function. Subjective measures of depression, sleep dysfunction, post-concussive symptoms (PCS), and executive function showed significant improvement with stimulation, retaining improved levels at two-week follow-up. EEG delta power exhibited elevation one week after stimulation cessation., Conclusions: While there is no indication that rTMS is beneficial for neuropsychological performance, it may improve PCS and subjective cognitive dysfunction. Long-term alterations in cortical oscillations may underlie the therapeutic effects of rTMS.

Objective: The efficacy of deep brain stimulation (DBS) in treating the symptoms of movement disorders can be life changing for patients. Thus, the 5%-15% incidence of stimulator-related infection requiring removal of the device can be particularly disheartening. Although DBS system reimplantation is generally successful, this is not always the case. The literature is replete with publications describing the incidence of infection and the associated features. However, the literature is sparse in terms of information on the incidence of recurrent or recrudescent infection after system reimplantation. The goal of this paper was to evaluate factors leading to unsuccessful reimplantation of a DBS system following initial infection., Methods: Data were reviewed for all DBS procedures performed by one surgeon (K.L.H.) over 19 years including the infectious agent, location of infection, treatment regimen, and subsequent reimplantation of a DBS system and long-term outcome., Results: In this series of 558 patients who had undergone DBS surgery, 37 (6.6%) subsequently developed an infection. Infections with methicillin-sensitive Staphylococcus aureus, Enterobacter species, or coagulase-negative staphylococci were predominant. Four patients had cerebritis, one had meningitis, and the rest had soft tissue infections of the pocket or scalp. All had their entire DBS system explanted, followed by 4-6 weeks of intravenous antibiotics and surveillance for recrudescence for an additional period of at least 30 days. Twenty-five patients subsequently underwent DBS system reimplantation, and the procedure was successful in 22. Three of the 4 patients with cerebritis developed a subsequent wound infection after system reimplantation. None of the other 22 patients developed a recurrence. The odds ratio for developing a recurrent infection after cerebritis was 28.5 (95% CI 1.931-420.5, p = 0.007)., Conclusions: This study, the largest series of DBS system reimplantations following infection, demonstrated that most patients can have successful reimplantations without recurrent infection. However, patients who have had DBS-related cerebritis have a nearly 30-fold increased risk of developing reinfection after reimplantation. Alternative strategies for these patients are discussed.

Objective: Randomized controlled trials have demonstrated that deep brain stimulation (DBS) of both the globus pallidus internus (GPI) and subthalamic nucleus (STN) for Parkinson's disease (PD) is superior to the best medical therapy. Tremor is particularly responsive to DBS, with reports of 70%-80% improvement. However, a small number of patients do not obtain the expected response with both STN and GPI targets. Indeed, the authors' patient population had a similar 81.2% tremor reduction with a 9.6% failure rate. In an analysis of these failures, they identified patients with preoperative on-medication tremor who subsequently received a GPI lead as a subpopulation at higher risk for inadequate tremor control. Thereafter, STN DBS was recommended for patients with on-medication tremor. However, for the patients with symptoms and comorbidities that favored GPI as the target, dual GPI and ventral intermediate nucleus of the thalamus (VIM) leads were proposed. This report details outcomes for those patients., Methods: This is a retrospective review of patients with PD who met the criteria for and underwent simultaneous GPI+VIM DBS surgery from 2015 to 2020 and had available follow-up data. The preoperative Unified Parkinson's Disease Rating Scale scores were obtained with the study participants on and off their medication. Postoperatively, the GPI lead was kept on at baseline and scores were obtained with and without VIM stimulation., Results: Thirteen PD patients with significant residual preoperative tremor on medication underwent simultaneous GPI+VIM DBS surgery (11 unilateral, 2 bilateral). A mean 90.6% (SD 15.0%) reduction in tremor scores was achieved with dual GPI+VIM stimulation compared to a 21.8% (SD 71.9%) reduction with GPI stimulation alone and a 30.9% (SD 37.8%) reduction with medication. Although rigidity and bradykinesia reductions were accomplished with just GPI stimulation, 13 of the 15 hemispheres required VIM stimulation to achieve excellent tremor control., Conclusions: GPI+VIM stimulation was required to adequately control tremor in all but 2 patients in this series, substantiating the authors' hypothesis that, in their population, medication-resistant tremor does not completely respond to GPI stimulation. Dual stimulation of the GPI and VIM proved to be an effective option for the patients who had symptoms and comorbidities that favored GPI as a target and had medication-resistant tremor.

Background: In this study, we describe a technique of optimizing the accuracy of frameless deep brain stimulation (DBS) lead placement through the use of a cannula poised at the entry to predict the location of the fully inserted device. This allows real-time correction of error prior to violation of the deep gray matter., Methods: We prospectively gathered data on radial error during the operative placements of 40 leads in 28 patients using frameless fiducial-less DBS surgery. Once the Nexframe had been aligned to target, a cannula was inserted through the center channel of the BenGun until it traversed the pial surface and a low-dose O-arm spin was obtained. Using 2 points along the length of the imaged cannula, a trajectory line was projected to target depth. If lead location could be improved, the cannula was inserted through an alternate track in the BenGun down to target depth. After intraoperative microelectrode recording and clinical assessment, another O-arm spin was obtained to compare the location of the inserted lead with the location predicted by the poised cannula., Results: The poised cannula projection and the actual implant had a mean radial discrepancy of 0.75 ± 0.64 mm. The poised cannula projection identified potentially clinically significant errors (avg 2.07 ± 0.73 mm) in 33% of cases, which were reduced to a radial error of 1.33 ± 0.66 mm (p = 0.02) after correction using an alternative BenGun track. The final target to implant error for all 40 leads was 1.20 ± 0.52 mm with only 2.5% of errors being >2.5 mm., Conclusion: The poised cannula technique results in a reduction of large errors (>2.5 mm), resulting in a decline in these errors to 2.5% of implants as compared to 17% in our previous publication using the fiducial-less method and 4% using fiducial-based methods of DBS lead placement., (© 2021 S. Karger AG, Basel.)

Introduction : Cortical cholinergic denervation resulting from degeneration of the nucleus basalis of Meynert (NBM) is a primary contributor to cognitive impairment and neuropsychiatric symptoms in the Lewy body diseases Parkinson's disease (PD), Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB). Considering the morbidity associated with cognitive impairment and neuropsychiatric symptoms in these diseases, it is important to investigate all potential therapies to improve these symptoms. Areas covered : The authors review the current landscape of pharmacological and surgical therapies for mitigating the cortical cholinergic deficiency in PD, PDD, and DLB. Expert opinion : The cholinesterase inhibitors rivastigmine, donepezil, and galantamine are currently the primary pharmacological treatments available to improve cognition and associated neuropsychiatric symptoms in Lewy body diseases. Other possible pharmacological strategies include increasing acetylcholine release with 5-HT 4 agonists or directly stimulating cholinergic receptors with muscarinic and nicotinic agonists. The side effect profile of muscarinic agonists is a deterrent to their future study, but 5-HT 4 and nicotinic agonists deserve further investigation. Targeting the basal forebrain with either deep brain stimulation (DBS)- or cell-based therapies is another strategy to mitigate cortical cholinergic deficiency. Before NBM DBS studies continue, it will be important to resolve issues related to targeting, stimulation pattern, and duration.

Objective: Laser interstitial thermal therapy (LITT) for mesial temporal lobe epilepsy (mTLE) has reported seizure freedom rates between 36% and 78% with at least 1 year of follow-up. Unfortunately, the lack of robust methods capable of incorporating the inherent variability of patient anatomy, the variability of the ablated volumes, and clinical outcomes have limited three-dimensional quantitative analysis of surgical targeting and its impact on seizure outcomes. We therefore aimed to leverage a novel image-based methodology for normalizing surgical therapies across a large multicenter cohort to quantify the effects of surgical targeting on seizure outcomes in LITT for mTLE., Methods: This multicenter, retrospective cohort study included 234 patients from 11 centers who underwent LITT for mTLE. To investigate therapy location, all ablation cavities were manually traced on postoperative magnetic resonance imaging (MRI), which were subsequently nonlinearly normalized to a common atlas space. The association of clinical variables and ablation location to seizure outcome was calculated using multivariate regression and Bayesian models, respectively., Results: Ablations including more anterior, medial, and inferior temporal lobe structures, which involved greater amygdalar volume, were more likely to be associated with Engel class I outcomes. At both 1 and 2 years after LITT, 58.0% achieved Engel I outcomes. A history of bilateral tonic-clonic seizures decreased chances of Engel I outcome. Radiographic hippocampal sclerosis was not associated with seizure outcome., Significance: LITT is a viable treatment for mTLE in patients who have been properly evaluated at a comprehensive epilepsy center. Consideration of surgical factors is imperative to the complete assessment of LITT. Based on our model, ablations must prioritize the amygdala and also include the hippocampal head, parahippocampal gyrus, and rhinal cortices to maximize chances of seizure freedom. Extending the ablation posteriorly has diminishing returns. Further work is necessary to refine this analysis and define the minimal zone of ablation necessary for seizure control., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Background: Frameless stereotactic surgery utilizing fiducial-based (FB) registration is an established tool in the armamentarium of deep brain stimulation (DBS) surgeons. Fiducial-less (FL) registration via intraoperative CT, such as the O-arm, has been routinely used in spine surgery, but its accuracy for DBS surgery has not been studied in a clinical setting., Objective: We undertook a study to analyze the accuracy of the FL technique in DBS surgery and compare it to the FB method., Methods: In this prospective cohort study, 97 patients underwent DBS surgery using the NexFrame and the O-arm registration stereotactic system. Patients underwent FB (n = 50) registration from 2015 to 2016 and FL (n = 47) O-arm registration from 2016 to 2017., Results: The radial errors (RE) and vector/euclidean errors of FB and FL registration were not significantly different. There was no difference in additional passes between methods, but there was an increase in the number of RE ≥2.5 mm in the FL method., Conclusion: Although there was no statistically significant difference in RE or the need for additional passes, the increased number of errors ≥2.5 mm with the FL method (17 vs. 4% in FB) indicates the need for further study. We concluded that O-arm images of the implants should be utilized to assess and correct for this error., (© 2019 S. Karger AG, Basel.)

Deep brain stimulation (DBS) of nucleus basalis of Meynert (NBM) is currently being evaluated as a potential therapy to improve memory and overall cognitive function in dementia. Although, the animal literature has demonstrated robust improvement in cognitive functions, phase 1 trial results in humans have not been as clear-cut. We hypothesize that this may reflect differences in electrode location within the NBM, type and timing of stimulation, and the lack of a biomarker for determining the stimulation's effectiveness in real time. In this article, we propose a methodology to address these issues in an effort to effectively interface with this powerful cognitive nucleus for the treatment of dementia. Specifically, we propose the use of diffusion tensor imaging to identify the nucleus and its tracts, quantitative electroencephalography (QEEG) to identify the physiologic response to stimulation during programming, and investigation of stimulation parameters that incorporate the phase locking and cross frequency coupling of gamma and slower oscillations characteristic of the NBM's innate physiology. We propose that modulating the baseline gamma burst stimulation frequency, specifically with a slower rhythm such as theta or delta will pose more effective coupling between NBM and different cortical regions involved in many learning processes.

Aim: World-wide, approximately 14% of children have prevalent asthma. As most bone accrual occurs in childhood, and data suggest a detrimental role in bone from asthma and/or medications, we investigated whether asthma was associated with radiologically confirmed fractures in a large cohort of children., Methods: Data from the Barwon Asthma Study (2005), a population-based, cross-sectional survey of all children attending 91 primary schools in the Barwon Statistical Division, were linked to the Geelong Osteoporosis Study Fracture Grid (2006-2007), a fracture register encompassing the Barwon Statistical Division (n = 16 438; 50.5% boys; aged 3.5-13.6 years). Asthma, ascertained from parent-reported symptoms using the International Study of Asthma and Allergies in Childhood questionnaire, was categorised as: (i) recent wheeze; and number of (ii) recent wheezy episodes; (iii) doctor visits for wheeze symptoms; and (iv) doctor visits for asthma check-ups. Using logistic regression analyses, stratified by sex and adjusted for age and medication use, we determined whether asthma was associated with radiologically confirmed fractures., Results: In total, 961 fractures were observed among 823 Barwon Asthma Study participants (5.9% of total sample; 61.1% boys). Recent wheeze and 1-3 recent wheezy episodes were associated with increased odds of fracture in boys (odds ratio (OR) 1.26, 95% confidence interval (CI) 1.03-1.55; OR 1.40, 95% CI 1.12-1.77, respectively), but not girls (OR 1.03, 95% CI 0.78-1.37; OR 0.67, 95% CI 0.38-1.19). Results were independent of age, and sustained after adjustment for medication., Conclusions: Independent of age, asthma was associated with fracture for boys, but not girls. There is an imperative for strategies to promote bone health among children with asthma., (© 2018 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

The names of the co-authors Steven Graves and Michelle Lorimer were missing from the manuscript supplied for publication. The lead authors regret this error and apologize for any inconvenience.

Objectives: Pretirees are a demographic interposed between the latter stages of working life and old age. We aimed to characterise subjective wellbeing and lifestyle behaviours for individuals aged in their late-fifties and sixties., Study Design: Cross-sectional study of 233 men and 229 women aged 55-69 yr from the Geelong Osteoporosis Study., Main Outcome Measures: Subjective wellbeing assessed using the World Health Organization Quality of Life questionnaire (WHOQOL-BREF, Australia). Scores below published population norms for Australia for WHOQOL domains (physical, psychological, social, environmental) were considered low., Results: For men, low WHOQOL scores were evident for 78 (33.5%) of participants regarding physical health, 94 (40.3%) for psychological wellbeing, 89 (38.2%) for social relationships, and 99 (42.5%) for the environment; the respective figures for women were 110 (48.0%), 124 (54.1%), 84 (36.7%), and 95 (41.5%). While there were few smokers (men 10.8%; women 6.5%), 42.5% of men and 17.7% of women exceeded recommended alcohol levels; 6.4% of men and 15.2% of women met the recommendation to consume each day at least two portions of fruit and five of vegetables. In multivariable models, being active was consistently associated with high WHOQOL scores, and low socioeconomic status with low WHOQOL scores. Pain and polypharmacy were associated with increased likelihood of poor scores for physical health, living with a partner increased the likelihood of good social relationships, and body mass index, employment, sleep, and alcohol and fruit/vegetable intakes were associated with WHOQOL scores in at least one domain., Conclusions: There is an opportunity for targeting health promotion to pretirees, particularly in socially disadvantaged regions, in order to optimise transition into old age. Our data highlight lifestyle interventions without which many pretirees might progress to old age at increased risk of diminished wellbeing., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Mice with targeted gene disruption have provided important information about the molecular mechanisms of circadian clock function. A full understanding of the roles of circadian-relevant genes requires manipulation of their expression in a tissue-specific manner, ideally including manipulation with high efficiency within the suprachiasmatic nuclei (SCN). To date, conditional manipulation of genes within the SCN has been difficult. In a previously developed mouse line, Cre recombinase was inserted into the vesicular GABA transporter (Vgat) locus. Since virtually all SCN neurons are GABAergic, this Vgat-Cre line seemed likely to have high efficiency at disrupting conditional alleles in SCN. To test this premise, the efficacy of Vgat-Cre in excising conditional (fl, for flanked by LoxP) alleles in the SCN was examined. Vgat-Cre-mediated excision of conditional alleles of Clock or Bmal1 led to loss of immunostaining for products of the targeted genes in the SCN. Vgat-Cre + ; Clock fl/fl ; Npas2 m/m mice and Vgat-Cre + ; Bmal1 fl/fl mice became arrhythmic immediately upon exposure to constant darkness, as expected based on the phenotype of mice in which these genes are disrupted throughout the body. The phenotype of mice with other combinations of Vgat-Cre + , conditional Clock, and mutant Npas2 alleles also resembled the corresponding whole-body knockout mice. These data indicate that the Vgat-Cre line is useful for Cre-mediated recombination within the SCN, making it useful for Cre-enabled technologies including gene disruption, gene replacement, and opto- and chemogenetic manipulation of the SCN circadian clock.

Objective: To determine whether adults with normoglycaemia, impaired fasting glucose (IFG) and diabetes differed according to the incidence, rate, length and primary reasons for hospital admission., Design: Retrospective cohort study., Setting: Barwon Statistical Division, Geelong, Australia., Participants: Cohort included 971 men and 924 women, aged 20+ years, participating in the Geelong Osteoporosis Study. Glycaemic status was assessed at cohort entry using fasting plasma glucose, use of antihyperglycaemic medication and/or self-report., Primary and Secondary Outcome Measures: Primary outcome measure was any admission to the major tertiary public hospital in the study region over the follow-up period. Secondary outcome measures were admission rate and length (days)., Results: Over a median follow-up of 7.4 years (IQR 5.3-9.6), participants with diabetes, compared with those with normoglycaemia, were two times as likely to be hospitalised (OR 2.07, 95% CI 1.42 to 3.02), had a higher admission rate (incidence rate ratio 1.61, 95% CI 1.17 to 2.23) and longer hospital stay (third quartile difference 7.7, 95% CI 1.3 to 14.1 and ninth decile difference 16.2, 95% CI 4.2 to 28.3). IFG group was similar to normoglycaemia for the incidence, rate and length of admission. Cardiovascular disease-related diagnoses were the most common primary reasons for hospitalisation across all glycaemic categories., Conclusions: Our results show increased incidence, rate and length of all-cause hospital admission in adults with diabetes as compared with normoglycaemia; however, we did not detect any associations for IFG. Interventions should focus on preventing IFG-to-diabetes progression and reducing cardiovascular risk in IFG and diabetes., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Hip fractures are associated with considerable morbidity and mortality. Hip fracture incidence varies across different levels of accessibility/remoteness and socioeconomic status (SES). As part of the Ageing, Chronic Disease and Injury Study, we aimed to map the pattern of hip fractures across the western region of the Australian state of Victoria, which contains a range of remoteness levels and SES., Methods: Data on hip fractures resulting in hospital admission were extracted from the Victorian Admitted Episodes Dataset (VAED) for men and women aged 40+years during 2010-2013 inclusive. An age-adjusted incidence rate (per 10,000population/year) was calculated for the entire region. Crude incidence rates and length of acute care hospital stay (excluding rehabilitation) were calculated for each Local Government Area (LGA). The impact of aggregated age, accessibility/remoteness index of Australia (ARIA) and SES on hip fracture rates aggregated across LGAs was determined using Poisson regression., Results: For men, the age-standardised rate of hospitalisations for hip fracture across the whole region was 19.2 per 10,000population/year (95%CI 18.0-20.4) and for women, 40.0 (95%CI 38.3-41.7). The highest incidence rates for both sexes occurred in the less accessible LGAs of Yarriambiack and Hindmarsh, as well as the LGA with the lowest SES, Central Goldfields. In both sexes, approximately two thirds of individuals were discharged from acute hospital care within 14days. Increasing age, higher remoteness and lower SES were all associated with higher hip fracture rates., Conclusion: Crude incidence rates varied by location. Given that a high proportion of patients had acute hospital care of ≤14days, and accessibility and SES were associated with hip fracture rates, these results can inform policy and provide a model for other groups to conduct similar research in their local environment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The stereotactic frame has served as the gold standard apparatus for accurate and precise targeting of deep brain structures since 1947. Despite passing the test of time, the stereotactic frame has several limitations from the perspective of both neurosurgeons and patients. Therefore, there was a need to develop a frameless system that had equivalent accuracy and reliability to the frame. This need was met with 3 commercially available frameless stereotactic systems designed specifically for deep brain stimulation surgery: Nexframe, STarFix, and ClearPoint. Over the past decade, the frameless and frame-based systems have been extensively investigated by numerous studies and found to be equivalent in experimental and clinical accuracy as well as in clinical outcomes. This chapter summarizes the findings of those studies along with the discussion of sources of stereotactic errors. The procedural aspects, advantages, and disadvantages of each frameless system are reviewed. Frameless stereotaxy is a safe, accurate, and effective technique for functional stereotactic approaches and provides a viable alternative to the frame-based systems., (© 2018 S. Karger AG, Basel.)

There was no significant difference between the areas under receiver operating characteristics (AUROCs) and diagnostic indexes (sensitivity, specificity, positive predictive value, negative predictive value) for either major osteoporotic or hip fracture FRAX scores when comparing the unadjusted and trabecular bone score (TBS)-adjusted scores., Introduction: FRAX 10-year probability of fracture can be calculated with adjustment for the TBS. Studies have shown that TBS can improve FRAX assessments in some populations. This study aimed to determine if TBS-adjusted FRAX score is better than the unadjusted score for predicting major osteoporotic fracture (MOF) and hip fracture in Australian men., Methods: This study involved 591 men aged 40-90 years, enrolled in the Geelong Osteoporosis Study. Incident MOF (n = 50) and hip fractures (n = 14) were ascertained using radiological reports. Median follow-up time was 9.5 years (IQR7.5-11.4). Diagnostic indexes were calculated using cut points of ≥20% for MOF and ≥3% for the hip. AUROC curves were also determined for adjusted and unadjusted scores as continuous variables., Results: Sensitivity was higher in the TBS-adjusted scores (MOF 4%, hip 78.6%) than the unadjusted scores (MOF 2%, hip 57.1%), with a decrease in specificity (MOF 98.9 vs 99.3%; hip 79.9 vs 83.9%). When considering TBS-adjusted and unadjusted FRAX as continuous scores, AUROCs were 0.738 and 0.740, respectively, for MOF and 0.849 and 0.848 for the hip., Conclusions: Prediction of fractures by MOF or hip FRAX was not substantially improved by TBS adjustment. There was no difference in AUROCs or diagnostic indexes for cut-off points of ≥20 for MOF and ≥3% for hip FRAX.

Diabetes is associated with increased skeletal fragility, despite higher bone mineral density (BMD). Alternative measures are necessary to more accurately determine fracture risk in individuals with diabetes. Therefore, we aimed to describe the relationship between trabecular bone score (TBS) and normoglycaemia, impaired fasting glucose (IFG) and diabetes and determine whether TBS-adjusted FRAX (Aus) score differed between these groups. This study included 555 men (68.7 ± 12.2 years) and 514 women (62.0 ± 12.0 years), enrolled in the observational Geelong Osteoporosis Study. IFG was considered as fasting plasma glucose (FPG) ≥ 5.5 mmol/L and diabetes as FPG ≥ 7.0 mmol/L, with the use of antihyperglycaemic medication and/or self-report. Using multivariable regression, the relationship between groups and TBS was determined. Men and women (all ages) with diabetes had lower mean TBS compared to those with normoglycaemia, in models adjusted for age, height and weight/waist circumference (all p < 0.05). Men with IFG had lower mean TBS in the age-adjusted models only (all p < 0.05). The addition of TBS to the FRAX score improved the discrimination between glycaemia groups, particularly for younger women (< 65 years). There was no difference in TBS detected between normoglycaemia and IFG; however, those with diabetes had lower TBS. Thus, the increased fracture risk in men and women with diabetes may be a result of BMD-independent bone deterioration. TBS adjustment of FRAX scores may be useful for younger women (< 65 years) with diabetes. This suggests that halting or reversing progression from IFG to diabetes could be important to prevent skeletal fragility in diabetes.

No studies have explored the relationship with maternal vitamin D (25(OH)D) in pregnancy and offspring trabecular bone score (TBS). Our data suggest that maternal 25(OH)D in early pregnancy, but not late, may be associated with offspring TBS in boys. These data act as hypothesis-generating findings for confirmation in larger, longer-term studies., Introduction: Trabecular bone score (TBS), a novel tool derived from dual-energy X-ray absorptiometry (DXA), reflects the microarchitecture of the vertebrae. It has been shown to predict fracture independent of standard DXA parameters in adult populations. Previously, we demonstrated that maternal serum 25-hydroxyvitamin D (25(OH)D) during pregnancy is associated with offspring bone mineral content at age 11 years. However, associations with TBS have not been explored, thus we aimed to determine associations between maternal 25(OH)D and offspring TBS., Methods: Data were collected from the Vitamin D in Pregnancy (VIP) study. Venous blood samples were taken at recruitment and at 28-32 weeks' gestation. Maternal 25(OH)D was measured by radioimmunoassay. Offspring (n = 195, n = 181 with complete measures) underwent spine DXA (GE Lunar), at age 11 years (median = 10.9 (IQR 10.9-11.4)). TBS was calculated using TBS iNsight software., Results: Offspring of mothers with sufficient 25(OH)D levels (≥50 nmol/L) at recruitment had a higher TBS (1.363 vs. 1.340, p = 0.04). In multivariable linear regression models, after adjustment for child relative lean mass, sex and pubertal stage, a 10 nmol/L increase in maternal 25(OH)D was associated with a 0.005 (95% CI 0.000, 0.010, p = 0.04) increase in TBS. However when stratified by sex (p for interaction = 0.16), the association was significant in boys, but not girls. There were no associations with TBS and maternal 25(OH)D at 28-32 weeks., Conclusions: We speculate that maternal 25(OH)D in early pregnancy may be associated with TBS in offspring at age 11 in boys. These hypothesis-generating findings warrant confirmation with larger interventional and long-term follow-up studies.

Compared to urban residents, those in rural/regional areas often experience inequitable healthcare from specialist service providers. Independent of small between-area differences in utilisation, socially advantaged groups had the greatest uptake of joint replacement. These data suggest low correlation between 'need' vs. 'uptake' of surgery in rural/regional areas., Background and Purpose: Compared to urban residents, those in rural and regional areas often experience inequitable healthcare from specialist service providers, often due to geographical issues. We investigated associations between socioeconomic position (SEP), region of residence and utilisation of primary total knee replacement (TKR) and/or total hip replacement (THR) for osteoarthritis., Design and Methods: As part of the Ageing, Chronic Disease and Injury study, we extracted data from the Australian Orthopaedic Association National Joint Replacement Registry (2011-2013) for adults that utilised primary TKR (n = 4179; 56% female) and/or THR (n = 3120; 54% female). Residential addresses were matched with the Australian Bureau of Statistics (ABS) 2011 census data: region of residence was defined according to local government areas (LGAs), and area-level SEP (quintiles) defined using an ABS-derived composite index. The ABS-determined control population (n = 591,265; 51% female) excluded individuals identified as cases. We performed multilevel logistic regression modelling using a stratified two-stage cluster design., Results: TKR was higher for those aged 70-79 years (AOR 1.4 95%CI 1.3-1.5; referent = 60-69 years) and in the most advantaged SEP quintile (AOR 2.1, 95%CI 1.8-2.3; referent = SEP quintile 3); results were similar for THR (70-79 years = AOR 1.7, 95%CI 1.5-1.8; SEP quintile 5 = AOR 2.5, 95%CI 2.2-2.8). Total variances contributed by the variance in LGAs were 2% (SD random effects ± 0.28) and 3% (SD ± 0.32), respectively., Conclusion: Independent of small between-LGA differences in utilisation, and in contrast to the expected greater prevalence of osteoarthritis in disadvantaged populations, we report greater TKR and THR in more advantaged groups. Further research should investigate whether more advantaged populations may be over-serviced.

Background: Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression. To test the safety and efficacy of DBS for treatment-resistant depression, a prospective, randomised, sham-controlled trial was conducted., Methods: Participants with treatment-resistant depression were implanted with a DBS system targeting bilateral subcallosal cingulate white matter and randomised to 6 months of active or sham DBS, followed by 6 months of open-label subcallosal cingulate DBS. Randomisation was computer generated with a block size of three at each site before the site started the study. The primary outcome was frequency of response (defined as a 40% or greater reduction in depression severity from baseline) averaged over months 4-6 of the double-blind phase. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients were followed up for up to 24 months. The study is registered at ClinicalTrials.gov, number NCT00617162., Findings: Before the futility analysis, 90 participants were randomly assigned to active (n=60) or sham (n=30) stimulation between April 10, 2008, and Nov 21, 2012. Both groups showed improvement, but there was no statistically significant difference in response during the double-blind, sham-controlled phase (12 [20%] patients in the stimulation group vs five [17%] patients in the control group). 28 patients experienced 40 serious adverse events; eight of these (in seven patients) were deemed to be related to the study device or surgery., Interpretation: This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial. Future studies are needed to investigate factors such as clinical features or electrode placement that might improve efficacy., Funding: Abbott (previously St Jude Medical)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We found that lower limb fractures, which were largely the result of minimal trauma, had high levels of hospitalisation, length of stay and surgery. It is therefore important to prevent fractures at all sites to avoid the associated morbidity and mortality., Purpose: Hip fractures are a major cause of morbidity and mortality, particularly in older women. In comparison, less is known about the epidemiology and burden of other lower limb fractures. The study aimed to investigate the epidemiology and burden of these fractures., Methods: Incident fractures of the hip, femur, tibia/fibula, ankle and foot in women (≥ 20 years) managed through the University Hospital Geelong, Australia, were ascertained from 1 Jan. 2014 to 31 Dec. 2014 from radiology reports. Age, cause of fracture, post-fracture hospitalisation, surgery, length of stay and discharge location were ascertained from medical records., Results: We identified 585 fractures of the lower limb (209 hip, 42 femur, 41 tibia/fibula, 162 ankle, 131 foot). Most fractures were sustained by women aged ≥ 50 years. Fractures were largely a result of minimal trauma. Most women with hip or femur fractures were hospitalised; fewer were hospitalised for fractures at other sites. Surgery for fracture followed the same pattern as hospitalisations. Length of stay was the highest for hip and femur fractures and the lowest for foot fractures. Women with hip or femur fractures were discharged to rehabilitation more often than home. Fractures at other sites were most commonly discharged home., Conclusions: Fractures of the lower limb occurred frequently in older women. Hospitalisation and subsequent surgery were common in cases of hip and femur fractures. It is important for prevention strategies to target fractures at a range of skeletal sites to reduce costs, hospitalisations, loss of independence and reduced quality of life.

Numerous clinical and experimental observations suggest that deficient neuronal signaling in the globus pallidus externa (GPe) is integral to both Parkinson's disease (PD) and dystonia. In our previous studies in jaundiced dystonic rats, widespread silencing of neurons in GP (rodent equivalent to GPe) preceded and persisted during dystonic motor activity. We therefore hypothesized that on a background of slow and highly irregular and bursty neuronal activity in GP, cortical motor drive produces profound inhibition of GP as the basis for action-induced dystonia in Gunn rats. Presently, the neurotoxin ibotenate was injected locally into the motor territory of GP at one to four sites, over one to two tracts, in 19 normal rats. We found that highly circumscribed dorsal motor territory lesions reproducibly induced parkinsonism, while ventral lesions consistently produced dystonia. Post-lesioning, slow neuronal burst oscillations in the entopeduncular nucleus distinguished parkinsonian from dystonic rats. Next, we compared the deep brain stimulation contact sites in the GP internus used to treat patients with PD (n=21 implants in 12 successive patients) versus dystonia (n=16 implants in nine patients) and found the efficacious territory for ameliorating PD to be located chiefly dorsal to that for dystonia. The comparative distribution for treating PD versus dystonia was therefore anatomically consistent with that for inducing these features via GP lesions in rodents. Our collective findings thus suggest that dystonia and parkinsonism are differentially produced by pathological silencing of GPe neurons along distinct motor sub-circuits, resulting in disparate pathological basal ganglia output signaling., (Published by Elsevier Ltd.)

Background: We aimed to examine the relationship between musculoskeletal deterioration and all-cause mortality in a cohort of women studied prospectively over a decade., Methods: A cohort of 750 women aged 50-94 years was followed for a decade after femoral neck bone mineral density (BMD) and appendicular lean mass (ALM) were measured using dual energy X-ray absorptiometry, in conjunction with comorbidities, health behaviour data, and other clinical measures. The outcome was all-cause mortality identified from the Australian National Deaths Index. Using Cox proportional hazards models and age as the time variable, mortality risks were estimated according to BMD groups (ideal-BMD, osteopenia, and osteoporosis) and ALM groups (T-scores > -1.0 high, -2.0 to -1.0 medium, <-2.0 low)., Results: During 6712 person years of follow-up, there were 190 deaths, the proportions increasing with diminishing BMD: 10.7% (23/215) ideal-BMD, 23.5% (89/378) osteopenia, 49.7% (78/157) osteoporosis; and with diminishing ALM: 17.0% (59/345) high, 26.2% (79/301) medium, 50.0% (52/104) low. In multivariable models adjusted for smoking, polypharmacy, and mobility, compared with those with ideal BMD, mortality risk was greater for those with osteopenia [hazard ratio (HR) 1.77, 95% confidence interval (CI) 1.11-2.81] and osteoporosis (HR 2.61, 95%CI 1.60-4.24). Similarly, compared with those with high ALM, adjusted mortality risk was greater for medium ALM (HR 1.36, 95%CI 0.97-1.91) and low ALM (HR 1.65, 95%CI 1.11-2.45). When BMD and ALM groups were tested together in the model, BMD remained a predictor of mortality (HR 1.74, 95%CI 1.09-2.78; HR 2.82, 95%CI 1.70-4.70; respectively), and low ALM had borderline significance (HR 1.52, 95%CI 1.00-2.31), which was further attenuated after adjusting for smoking, polypharmacy, and mobility., Conclusions: Poor musculoskeletal health increased the risk for mortality independent of age. This appears to be driven mainly by a decline in bone mass. Low lean mass independently exacerbated mortality risk, and this appeared to operate through poor health exposures., (© 2016 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: Compared to non-indigenous populations, indigenous populations experience disproportionately greater morbidity, and a reduced life expectancy; however, conflicting data exist regarding whether a higher risk of fracture is experienced by either population. We systematically evaluate evidence for whether differences in fracture rates at any skeletal site exist between indigenous and non-indigenous populations of any age, and to identify potential risk factors that might explain these differences., Methods: On 31 August 2016 we conducted a comprehensive computer-aided search of peer-reviewed literature without date limits. We searched PubMed, OVID, MEDLINE, CINAHL, EMBASE, and reference lists of relevant publications. The protocol for this systematic review is registered in PROSPERO, the International Prospective Register of systematic reviews (CRD42016043215). Using the World Health Organization reference population as standard, hip fracture incidence rates were re-standardized for comparability between countries., Results: Our search yielded 3227 articles; 283 potentially eligible articles were cross-referenced against predetermined criteria, leaving 27 articles for final inclusion. Differences in hip fracture rates appeared as continent-specific, with lower rates observed for indigenous persons in all countries except for Canada and Australia where the opposite was observed. Indigenous persons consistently had higher rates of trauma-related fractures; the highest were observed in Australia where craniofacial fracture rates were 22-times greater for indigenous compared to non-indigenous women. After adjustment for socio-demographic and clinical risk factors, approximately a three-fold greater risk of osteoporotic fracture and five-fold greater risk of craniofacial fractures was observed for indigenous compared to non-indigenous persons; diabetes, substance abuse, comorbidity, lower income, locality, and fracture history were independently associated with an increased risk of fracture., Conclusions: The observed paucity of data and suggestion of continent-specific differences indicate an urgent need for further research regarding indigenous status and fracture epidemiology and aetiology. Our findings also have implications for communities, governments and healthcare professionals to enhance the prevention of trauma-related fractures in indigenous persons, and an increased focus on modifiable lifestyle behaviours to prevent osteoporotic fractures in all populations.

Aims: Impaired fasting glucose (IFG) and diabetes are increasing in prevalence worldwide and lead to serious health problems. The aim of this longitudinal study was to investigate the association between impaired fasting glucose or diabetes and mortality over a 10-year period in Australian women., Methods: This study included 1167 women (ages 20-94 yr) enrolled in the Geelong Osteoporosis Study. Hazard ratios for all-cause mortality in diabetes, IFG, and normoglycaemia were calculated using a Cox proportional hazards model., Results: Women with diabetes were older and had higher measures of adiposity, LDL cholesterol, and triglycerides compared to the IFG and normoglycaemia groups (all p < 0.001). Mortality rate was greater in women with diabetes compared to both the IFG and normoglycaemia groups (HR 1.8; 95% CI 1.3-2.7). Mortality was not different in women with IFG compared to those with normoglycaemia (HR 1.0; 95% CI 0.7-1.4)., Conclusions: This study reports an association between diabetes and all-cause mortality. However, no association was detected between IFG and all-cause mortality. We also showed that mortality in Australian women with diabetes continues to be elevated and women with IFG are a valuable target for prevention of premature mortality associated with diabetes.

Background: Falls are common among older adults and can lead to serious injuries, including fractures. We aimed to determine associations between anxiety disorders and falls in older adults., Methods: Participants were 487 men and 376 women aged ≥60 years enrolled in the Geelong Osteoporosis Study, Australia. Using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Non-patient edition (SCID-I/NP), lifetime history of anxiety disorders was determined. Falls were determined by self-report. In men, a falls-risk score (Elderly Falls Screening Test (EFST)) was also calculated., Results: Among fallers, 24 of 299 (8.0%) had a lifetime history of anxiety disorder compared to 36 of 634 (5.7%) non-fallers (p=0.014). Examination of the association between anxiety and falls suggested differential relationships for men and women. In men, following adjustment for psychotropic medications, mobility and blood pressure, lifetime anxiety disorder was associated with falling (OR 2.96; 95%CI 1.07-8.21) and with EFST score (OR 3.46; 95%CI 1.13-10.6). In women, an association between lifetime anxiety disorder and falls was explained by psychotropic medication use, poor mobility and socioeconomic status., Limitations: Sub-group analyses involving types of anxiety and anxiety disorders over the past 12-months were not performed due to power limitations., Conclusion: Although anxiety disorders were independently associated with a 3-fold increase in likelihood of reported falls and high falls risk among men, an independent association was not detected among women. These results may aid in prevention of falls through specific interventions aimed at reducing anxiety, particularly in men., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: Over recent years, there has been concerted effort to 'close the gap' in the disproportionately reduced life expectancy and increased morbidity experienced by indigenous compared to non-indigenous persons. Specific to musculoskeletal health, some data suggest that indigenous peoples have a higher risk of sustaining a fracture compared to non-indigenous peoples. This creates an imperative to identify factors that could explain differences in fracture rates. This protocol presents our aim to conduct a systematic review, first, to determine whether differences in fracture rates exist for indigenous versus non-indigenous persons and, second, to identify any risk factors that might explain these differences., Methods and Analysis: We will conduct a systematic search of PubMed, OVID, MEDLINE, CINAHL and EMBASE to identify articles that compare all-cause fracture rates at any skeletal site between indigenous and non-indigenous persons of any age. Eligibility of studies will be determined by 2 independent reviewers. Studies will be assessed for methodological quality using a previously published process. We will conduct a meta-analysis and use established statistical methods to identify and control for heterogeneity where appropriate. Should heterogeneity prevents numerical syntheses, we will undertake a best-evidence analysis to determine the level of evidence for differences in fracture between indigenous and non-indigenous persons., Ethics and Dissemination: This systematic review will use published data; thus, ethical permissions are not required. In addition to peer-reviewed publication, findings will be presented at (inter)national conferences, disseminated electronically and in print, and will be made available to key country-specific decision-makers with authority for indigenous health., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)