Search

Auto-antibody mediated astrocyte injury is implicated as a primary event in neuromyelitis optica (NMO) by biomarker, post-mortem and experimental studies that differentiate the condition from multiple sclerosis. We describe the clinical, radiological and neuropathological features of a severe cerebral attack in a natalizumab-treated patient with relapsing myelitis and serum aquaporin-4 antibodies. Our findings support autopsy evidence that abrupt astrocyte destruction precedes demyelination in NMO, and emphasize the importance of serological testing in patients with limited disease. Adherence to current NMO diagnostic criteria may delay treatment, or lead to inappropriate therapy with beta-interferon or natalizumab. [ABSTRACT FROM AUTHOR]

Displaced medial malleolus fractures are considered unstable and typically require open reduction and internal fixation for anatomic reduction and early joint range of motion. These fractures are usually fixated with either compression lag screws or tension band wiring depending on the fracture pattern, size of the distal fragment, and bone quality. When fracture fixation fails, it is typically in pullout strength. Failure of primary bone healing can result in nonunion, malunion, and need for revision surgery. The current study wished to explore a potentially stronger fixation technique in regard to pullout strength for medial malleolar fractures compared with traditional cancellous screws. This was a comparative study of the relative pullout strength of 2 fully threaded 3.5-mm bicortical screws versus 2 partially threaded 4.0-mm cancellous screws for the fixation of medial malleolar fractures. Ten fresh-frozen limbs from 5 cadavers, mean age 79 years (range of 65 -- 97 years), were tested using the Instron 8500 Plus system. The median force recorded at 2 mm of distraction using unicortical partially threaded cancellous screws was 116.2 N (range 70.2 to 355.5N) compared with 327.6 N (range 117.5 to 804.3 N) in the fully threaded bicortical screw (P = .04). The unicortical screw fixation displayed only 64.53% of the median strength noted with the bicortical screw fixation at clinical failure. The current study demonstrated statistically significantly greater pullout strength for 3.5-mm bicortical screws when compared with 4.0-mm partially threaded cancellous screws used to fixate medial malleolar fractures in a cadaveric model. [ABSTRACT FROM AUTHOR]

Studies do not provide a consensus opinion of the relationship between stress and relapse in relapsing–remitting multiple sclerosis (RRMS). Few studies have defined the critical features of these stressful situations, or examined the role of stress-mediating and -moderating variables. Available evidence indicates that the relationship between life stress and relapse is complex, and is likely to depend on factors such as stressor chronicity, frequency, severity and type, and individual patient characteristics such as depression, health locus of control and coping strategy use. Little is known about how these factors, individually or in combination, are related to MS disease activity. Viral infections are also likely to precipitate relapse in MS, and significant life-stress may further enhance this relationship. The nature and strength of these interrelationships have strong clinical implications. MS patients are particularly vulnerable to a deteriorating cycle of stressful life events, illness episodes and disability. Timely multidisciplinary care interventions aimed at both minimizing psychological distress and physical symptoms may halt this downward reciprocal cycle. Little is known of the pathogenesis of these putative stress-induced changes in disease activity, and almost all stressor studies suffer from some biases or limitations. [ABSTRACT FROM AUTHOR]

Experimental allergic neuritis was induced in 30 rabbits with extract of bovine peripheral nerve in complete Freund's adjuvant. Of the 22 animals that completed the study, nine animals were plasmapheresed within two weeks of inoculation and 13 animals served as controls. The plasmapheresed animals developed a less severe form of EAN than the controls. Differences were apparent in clinical weakness, weight loss, degree of dispersion of the muscle action potential and histological changes. [ABSTRACT FROM AUTHOR]

While the Lapidus bunionectomy is a common procedure utilized to address hallux valgus, the incidence of secondary surgery is not well established. Our primary goal was to determine the incidence of revision surgery and hardware removal following the Lapidus bunionectomy in addition to the risk factors associated with each. A retrospective nested case-control study of adult patients who underwent a Lapidus bunionectomy for symptomatic hallux valgus over a 9-year period was performed. The incidence rates and 95% confidence intervals (CI) of secondary surgery in the 3 years following the procedure along with the estimated independent associations and odds ratios between baseline demographic, clinical, and radiographic characteristics were calculated. Of the original cohort of 2540 patients, 127 were identified (5.0%; CI: 4.1%, 5.8%) who underwent revision surgery and 165 (6.5%; CI: 5.5%, 7.5%) who underwent hardware removal following Lapidus bunionectomy. Initially, the hallux valgus angle, intermetatarsal angle, and tibial sesamoid position were risk factors for revision surgery. However, in adjusted analyses for revision surgery, using a screw for third point of fixation emerged as the only independent risk factor (odds ratio [OR] = 3.01; CI: 1.59, 5.69). In adjusted analyses for hardware removal, female sex (OR = 2.33; CI: 1.08, 5.00) and third point of fixation (OR = 2.92; CI: 1.82, 4.69) emerged as independent risk factors. While the overall risks associated with Lapidus bunionectomy are low and the need for revision surgery are low, this study helps to identify specific risk factors for secondary surgery and hardware removal to help in evaluation and discussion with patients., (Copyright © 2024 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Foot and ankle surgeons are commonly confronted with the surgical dilemma on when and how to best surgically address trimalleolar ankle fractures with a posterior malleolar component. This may involve either direct fixation of the posterior malleolus or indirect stabilization with the fixation of the medial and lateral malleoli and trans-syndesmotic fixation. Recently there has been a paradigm shift in the management of these injuries with a more thorough understanding of anatomy, stability, and long-term sequela of these injuries. This article aims to evaluate the current literature on posterior malleolar ankle fractures, approaches to fixing the posterior malleolus, and outcomes and complications of these procedures., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Open reduction with internal fixation (ORIF) of Lisfranc injuries are associated with an increased risk for secondary surgery including hardware removal and salvage arthrodesis. In the current literature, rates of salvage arthrodesis vary due to small sample sizes and a low incidence of Lisfranc injuries. There is little evidence to identify specific surgical and patient-related variables that may result in later arthrodesis. The purpose of this study is to determine the rate of tarsometatarsal joint arthrodesis following Lisfranc ORIF in a relatively large sample size. This retrospective review included patients who underwent ORIF for a Lisfranc injury between January 2007 and December 2012. A total of 146 patients met our criteria. Trans-articular fixation was used in 109 (74.6%) patients, 33 (22.6%) received percutaneous fixation and 4 (2.7%) extraarticular fixation. Five out of 120 (4.2%) patients required a salvage arthrodesis for post-traumatic arthritis that had a follow-up greater than 5 y but up to 10 y. The mean age of patients who underwent arthrodesis after ORIF was 24.5 ± 11.95 (16-48) y compared to 40.9 ± 15.8 (16-85) y. Patients who required an arthrodesis also had earlier hardware removal than patients who did not have an arthrodesis, 71.2 ± 28.3 (38-100) days and 131.4 ±101.2 (37-606) days, respectively. Patients who required salvage arthrodesis tended to be younger and hardware was removed earlier compared to those patients who did not require an arthrodesis. Four of the 5 patients who underwent a secondary arthrodesis had a loss of correction after hardware removal., (Copyright © 2023 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Sickle cell disease, a common genetic disorder in African Americans, manifests an increased risk of sudden death, the basis of which is incompletely understood. Prolongation of heart rate-corrected QT (QTc) interval on the electrocardiogram, a standard clinical measure of cardiac repolarization, may contribute to sudden death by predisposing to torsades de pointes ventricular tachycardia., Methods: We established a cohort study of 293 adult and 121 pediatric sickle cell disease patients drawn from the same geographic region as the Jackson Heart Study (JHS) cohort, in which significant correlates of QT duration have been characterized and quantitatively modeled. Herein, we establish clinical and laboratory correlates of QTc duration in our cohort using stepwise multivariate linear regression analysis. We then compared our adult sickle cell disease data to effect-size predictions from the published JHS statistical model of QT interval duration., Results: In adult sickle cell disease, gender, diuretic use, QRS duration, serum ALT levels, anion gap, and diastolic blood pressure show positive correlation; hemoglobin levels show inverse correlation; in pediatric sickle cell disease, age, hemoglobin levels, and serum bicarbonate and creatinine levels show inverse correlation. The mean QTc in our adult sickle cell disease cohort is 7.8 milliseconds longer than in the JHS cohort, even though the JHS statistical model predicts that the mean QTc in our cohort should be > 11 milliseconds shorter than in the much older JHS cohort, a differential of > 18 milliseconds., Conclusion: Sickle cell disease patients have substantial QTc prolongation relative to their age, driven by factors some overlapping, in adult and pediatric sickle cell disease, and distinct from those that have been defined in the general African American community., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

A substantial proportion of the adult United States population with type 2 diabetes (T2D) are undiagnosed, calling into question the comprehensiveness of current screening practices, which primarily rely on age, family history, and body mass index (BMI). We hypothesized that a polygenic score (PGS) may serve as a complementary tool to identify high-risk individuals. The T2D polygenic score maintained predictive utility after adjusting for family history and combining genetics with family history led to even more improved disease risk prediction. We observed that the PGS was meaningfully related to age of onset with implications for screening practices: there was a linear and statistically significant relationship between the PGS and T2D onset (-1.3 years per standard deviation of the PGS). Evaluation of U.S. Preventive Task Force and a simplified version of American Diabetes Association screening guidelines showed that addition of a screening criterion for those above the 90th percentile of the PGS provided a small increase the sensitivity of the screening algorithm. Among T2D-negative individuals, the T2D PGS was associated with prediabetes, where each standard deviation increase of the PGS was associated with a 23% increase in the odds of prediabetes diagnosis. Additionally, each standard deviation increase in the PGS corresponded to a 43% increase in the odds of incident T2D at one-year follow-up. Using complications and forms of clinical intervention (i.e., lifestyle modification, metformin treatment, or insulin treatment) as proxies for advanced illness we also found statistically significant associations between the T2D PGS and insulin treatment and diabetic neuropathy. Importantly, we were able to replicate many findings in a Hispanic/Latino cohort from our database, highlighting the value of the T2D PGS as a clinical tool for individuals with ancestry other than European. In this group, the T2D PGS provided additional disease risk information beyond that offered by traditional screening methodologies. The T2D PGS also had predictive value for the age of onset and for prediabetes among T2D-negative Hispanic/Latino participants. These findings strengthen the notion that a T2D PGS could play a role in the clinical setting across multiple ancestries, potentially improving T2D screening practices, risk stratification, and disease management., Competing Interests: JA, OSa, OSv, SD, RK, LB, MM, SA, PF, SS, JP and BK are current or former employees of 23andMe, Inc. with financial interest in the company., (Copyright © 2022 Ashenhurst, Sazonova, Svrchek, Detweiler, Kita, Babalola, McIntyre, Aslibekyan, Fontanillas, Shringarpure, Pollard and Koelsch.)

Multiple fixation techniques for first metatarsophalangeal joint arthrodesis have been described with an average fusion rate of 93.5%. This retrospective cohort study assesses the association between crossed screws (vs dorsal plating) and medical comorbidities and the outcome radiographic union. Bivariate tests of association and multivariable logistic regression were employed to assess differences across fixation type and outcomes. We identified 305 patients who underwent a first metatarsophalangeal joint arthrodesis during the study period. Crossed screw fixation was used in 158 (51.8%) patients while dorsal plating (tubular or anatomic locking plate) was used in 147 (48.2%) patients. Dorsal plating was utilized more often in patients with rheumatoid arthritis (p = .019) and history of smoking (p = .044). At 12 weeks post-operatively there were no significant differences in fusion rates between the two groups (crossed screw group = 95.3% vs dorsal plate group (referent) = 93.5%, Adjusted odds ratio (AOR) 1.39, 95% confidence interval [CI] 0.45-4.26). Not smoking was associated with a greater odds of fusion at 12 weeks (96.2% for nonsmokers vs 75.0% for smokers (referent), AOR 0.07, 95% CI 0.02-0.28). Lower body mass index was associated with a greater odds of fusion at 12 weeks (AOR 0.90, 95% CI 0.82-0.99). Surgeons allowed weightbearing earlier with dorsal plate fixation (2 weeks (interquartile range [IQR] 2.6) versus 5 weeks (IQR 2.6) for crossed screw fixation, p = .001). Patients with multiple medical comorbidities were more likely to require revision surgery than patients having 0-1 comorbidities (p < .05). Crossed screws can provide an inexpensive yet effective option for first metatarsophalangeal joint arthrodesis., (Copyright © 2021 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the CNS. Overlap in the clinical and MRI features of NMOSD and MS means that distinguishing these conditions can be difficult. With the aim of evaluating the diagnostic utility of MRI features in distinguishing NMOSD from MS, we have conducted a cross-sectional analysis of imaging data and developed predictive models to distinguish the two conditions. NMOSD and MS MRI lesions were identified and defined through a literature search. Aquaporin-4 (AQP4) antibody positive NMOSD cases and age- and sex-matched MS cases were collected. MRI of orbits, brain and spine were reported by at least two blinded reviewers. MRI brain or spine was available for 166/168 (99%) of cases. Longitudinally extensive (OR = 203), "bright spotty" (OR = 93.8), whole (axial; OR = 57.8) or gadolinium (Gd) enhancing (OR = 28.6) spinal cord lesions, bilateral (OR = 31.3) or Gd-enhancing (OR = 15.4) optic nerve lesions, and nucleus tractus solitarius (OR = 19.2), periaqueductal (OR = 16.8) or hypothalamic (OR = 7.2) brain lesions were associated with NMOSD. Ovoid (OR = 0.029), Dawson's fingers (OR = 0.031), pyramidal corpus callosum (OR = 0.058), periventricular (OR = 0.136), temporal lobe (OR = 0.137) and T1 black holes (OR = 0.154) brain lesions were associated with MS. A score-based algorithm and a decision tree determined by machine learning accurately predicted more than 85% of both diagnoses using first available imaging alone. We have confirmed NMOSD and MS specific MRI features and combined these in predictive models that can accurately identify more than 85% of cases as either AQP4 seropositive NMOSD or MS., Competing Interests: MHB has received research support, speaking engagement honoraria, advisory board honoraria and travel sponsorship from Biogen Idec, Merck, Novartis, Roche and Sanofi-Genzyme, and is a consulting neurologist for RxMx and is Research Director of the Sydney Neuroimaging Analysis Centre. MB has received travel sponsorship and honoraria from Sanofi-Genzyme, Teva, Novartis, Biogen Idec and Roche. BB has received honoraria as a board member for GlaxoSmithKline, Biogen Idec, ViiV Healthcare and Merck Serono, has received speaker honoraria from ViiV Healthcare, Boehringer Ingelheim, Abbott, Abbvie, and Biogen Idec; has received travel sponsorship from Abbott and ViiV Healthcare, and has received research support funding from EI Lilly, GlaxoSmithKline, ViiV Healthcare and Merck Serono. FB has received speaker's honoraria from Biogen-Idec and EMD Serono. SAB has received honoraria for attendance at advisory boards and travel sponsorship from Bayer-Schering, Biogen-Idec, Merck-Serono, Novartis, and Sanofi-Genzyme, has received speakers honoraria from Biogen-Idec and Genzyme, is an investigator in clinical trials sponsored by Biogen Idec, Novartis and Genzyme, and was the recipient of an unencumbered research grant from Biogen-Idec. HB has received honoraria for serving on scientific advisory boards for Biogen Idec, Novartis and Sanofi-Genzyme, has received conference travel sponsorship from Novartis and Biogen Idec, has received honoraria for speaking and acting as Chair at educational events organised by Novartis, Biogen Idec, Medscape and Merck Serono, serves on steering committees for trials conducted by Biogen Idec and Novartis, is chair (honorary) of the MSBase Foundation, which has received research support from Merck Serono, Novartis, Biogen Idec, Genzyme Sanofi and CSL Biopharma and has received research support form Merck Serono. WC has been the recipient of travel sponsorship from, and provided advice to, Bayer Schering Pharma, Biogen-Idec, Novartis, Genzyme, Sanofi-Aventis, BioCSL and Merck-Serono. RD has received research funding from the National Health and Medical Research Council, MS Research Australia, Star Scientific Foundation, Pfizer Neuroscience, Tourette Syndrome Association, University of Sydney, and the Petre Foundation and has received honoraria from Biogen-Idec and Bristol-Myers Squibb as an invited speaker. MF-P has received travel sponsorship from Biogen Australia and New Zealand. RH has received honoraria, educational support and clinic funding from Novartis, Biogen Idec, Genzyme and BioCSL. AGKK has received scientific consulting fees and/or lecture honoraria from Bayer, BioCSL, Biogen-Idec, Genzyme, Lgpharma, Merck, Mitsubishi Tanabe Pharma, NeuroScientific Biopharmaceuticals, Novartis, Roche, Sanofi-Aventis, and Teva. TK has received travel sponsorship from Novartis, BioCSL, Novartis, Merck Serono and Biogen Idec, has received speaker honoraria from Biogen Idec, BioCSL, Merck Serono, Teva, Genzyme and Novartis, has received research support from Biogen Idec, Genzyme, GlaxoSmithKline, Bayer-Schering and Merck Serono, and has received scientific consulting fees from GlaxoSmithKline China, Biogen-Idec and Novartis. JK has received remuneration for advisory board activities and presentations from Bayer Healthcare, Biogen Idec, BioCSL, Genzyme and Novartis. CK has received travel support, honoraria and advisory board payments from Biogen Idec, Bayer, Genzyme, Novartis and Serono. JL-S has received unencumbered funding as well as honoraria for presentations and membership on advisory boards from Sanofi Aventis, Biogen Idec, Bayer Health Care, CSL, Genzyme, Merck Serono, Novartis Australia and Teva. RM has received honoraria for attendance at advisory boards and travel sponsorship from Bayer-Schering, Biogen-Idec, CSL, Merck-Serono, Novartis, and Sanofi-Genzyme. MM has received travel sponsorship, honoraria, trial payments, research and clinical support from Bayer Schering, Biogen Idec, BioCSL, Genzyme, Novartis, and Sanofi Aventis Genzyme. DM has received honoraria for attendance at advisory boards from Biogen-Idec and Novartis, and travel sponsorship from Bayer-Schering, Biogen-Idec, and Sanofi-Genzyme. PM has received honoraria or travel sponsorship from Novartis, Sanofi-Aventis and Biogen Idec. JP has received travel sponsorship, honoraria for presentations and membership on advisory boards from Biogen Idec and Novartis and Sanofi Aventis. JDP has received honoraria for seminars or advisory boards from Teva, Biogen, Sanofi-Genzyme, Novartis, Merck, Bayer and research grants or fellowships from Merck, Novartis, Bayer, Biogen, Sanofi-Genzyme, and Teva. SR has received honoraria for advisory consultancy from UCB and speaker's honoraria from Biogen Idec. SWR has received travel sponsorship, honoraria, trial payments, research and clinical support from Aspreva, Baxter, Bayer Schering, Biogen Idec, BioCSL, Genzyme, Novartis, Sanofi Aventis Genzyme and Servier, and is a director of Medical Safety Systems Pty Ltd. CPS has received travel sponsorship from Biogen Idec, Novartis and Bayer-Schering. IS has received remuneration for Advisory Board activities from Biogen, CSL, and Bayer Schering and educational activities with Biogen, CSL and travel sponsorship from Biogen, Novartis and Bayer Schering. JMS has received honoraria for lectures and participation in advisory boards, and travel sponsorship from Novartis, BioCSL, Genzyme, and Biogen Idec. BT has received travel sponsorship from Novartis and Bayer Schering. AV and the University of Oxford hold patents and receive royalties for antibody testing. PW and the University of Oxford hold patents for antibody assays and have received royalties, has received honoraria from Alexion, Biogen Idec F. Hoffmann-La Roche, Retrogenix, UBC and Euroimmun AG, and travel grants from the Guthy-Jackson Charitable Foundation. EW has received honoraria for participation in advisory boards from Biogen-Idec and Novartis, travel sponsorship from Biogen-Idec, Bayer-Schering and Teva and is an investigator in clinical trials funded by Biogen-Idec and Teva. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Clarke, Arnett, Bukhari, Khalilidehkordi, Jimenez Sanchez, O'Gorman, Sun, Prain, Woodhall, Silvestrini, Bundell, Abernethy, Bhuta, Blum, Boggild, Boundy, Brew, Brownlee, Butzkueven, Carroll, Chen, Coulthard, Dale, Das, Fabis-Pedrini, Gillis, Hawke, Heard, Henderson, Heshmat, Hodgkinson, Kilpatrick, King, Kneebone, Kornberg, Lechner-Scott, Lin, Lynch, Macdonell, Mason, McCombe, Pereira, Pollard, Ramanathan, Reddel, Shaw, Spies, Stankovich, Sutton, Vucic, Walsh, Wong, Yiu, Barnett, Kermode, Marriott, Parratt, Slee, Taylor, Willoughby, Brilot, Vincent, Waters and Broadley.)

Rationale & Objective: The relation of vascular stiffness, endothelial function, and kidney function is incompletely elucidated in African Americans. Our hypothesis was that increased vascular stiffness and endothelial dysfunction are associated with low estimated glomerular filtration rate (eGFR) and albuminuria in African Americans., Study Design: Cross-sectional cohort analysis of data from the Jackson Heart Study., Settings & Patients: 2,244 Jackson Heart Study participants (2012-2017 after Exam 3) who had undergone noninvasive hemodynamic assessment using arterial tonometry., Predictors: Baseline carotid-femoral pulse wave velocity, pulsatile hemodynamics forward wave amplitude, and hyperemic brachial artery flow were measured. Reduced eGFR was defined as eGFR between 15 and 60 mL/min/1.73 m 2 ., Outcomes: Prevalent albuminuria, urinary albumin-creatinine ratio., Analytical Approach: 2-sample t test for continuous variables and χ 2 test for categorical variables in addition to logistic and linear regression models to assess the risk for chronic kidney disease with each proposed hemodynamic variable., Results: Among 2,244 participants, mean age was 66 ± 11 years and 64% were women. Reduced eGFR was present in 233 (10.4%), and elevated urinary albumin-creatinine ratio, in 232 (10.4%). In multivariable-adjusted analyses, higher carotid-femoral pulse wave velocity was associated with the presence of reduced eGFR (OR, 1.37 [95% CI, 1.08-1.75] per SD; P  = 0.01) and with prevalent albuminuria (OR, 1.66 [95% CI, 1.32-2.11]; P  < 0.001). Higher forward wave amplitude was significantly associated with prevalent albuminuria (OR, 1.37 [95% CI, 1.14-1.65]; P  = 0.001)., Limitations: Cross-sectional analyses cannot inform causality., Conclusions: Higher arterial stiffness and pulsatility are associated with higher odds of reduced eGFR in African Americans. Future studies should focus on whether improving arterial stiffness contributes to kidney protection in African Americans., (© 2021 The Authors.)

Charcot neuroarthropathy is a debilitating condition that frequently leads to skeletal deformity and pedal ulceration in the insensate foot. Results are often poor and no clear guidelines for surgical management exist. Additionally, amputation rates vary widely making it difficult to accurately inform patients of risks. Few studies have assessed outcomes to identify patients for whom reconstruction is likely to fail. The literature is limited, with small sample sizes and mortality infrequently addressed. We performed a retrospective observational study of patients with Charcot neuroarthropathy to assess overall amputation and mortality rates at 30 days, 1 year, and 3 years postreconstruction and evaluated associated risk factors. Rates of infection, re-ulceration, and return to walking were also assessed. We identified 151 patients over a 5-year period. Demographic and clinical characteristics were collected. Descriptive statistics, Cox proportional hazard model, and logistic regression were used. Overall, 22 (14.6%) patients died, and 23 (15.2%) patients advanced to limb amputation postoperatively. End-stage renal disease, peripheral vascular disease, reconstruction during active phase Charcot process, and reconstruction at the ankle or subtalar joint were all associated with poor outcomes. The risk of mortality was 2.5 times higher in patients with end-stage renal disease, and 3.4 times higher among patients with peripheral vascular disease. Patients with ankle or subtalar joint reconstruction were 70% less likely to return to walking compared to medial column reconstruction. Due to these findings, we suggest that patients with such comorbidities be advised of increased risk for complications including failure to return to walking, amputation, and death., (Copyright © 2020 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: We hypothesised that (1) the prevalent cardiovascular disease (CVD) is associated with global electrical heterogeneity (GEH) after adjustment for demographic, anthropometric, socioeconomic and traditional cardiovascular risk factors, (2) there are sex differences in GEH and (3) sex modifies an association of prevalent CVD with GEH., Design: Cross-sectional, cohort study., Setting: Prospective African-American The Jackson Heart Study (JHS) with a nested family cohort in 2000-2004 enrolled residents of the Jackson, Mississippi metropolitan area., Participants: Participants from the JHS with analysable ECGs recorded in 2009-2013 (n=3679; 62±12 y; 36% men; 863 family units). QRS, T and spatial ventricular gradient (SVG) vectors' magnitude and direction, spatial QRS-T angle and sum absolute QRST integral (SAI QRST) were measured., Outcome: Prevalent CVD was defined as the history of (1) coronary heart disease defined as diagnosed/silent myocardial infarction, or (2) revascularisation procedure defined as prior coronary/peripheral arterial revascularisation, or (3) carotid angioplasty/carotid endarterectomy, or (4) stroke., Results: In adjusted mixed linear models, women had a smaller spatial QRS-T angle (-12.2 (95% CI -19.4 to -5.1)°; p=0.001) and SAI QRST (-29.8 (-39.3 to -20.3) mV*ms; p<0.0001) than men, but larger SVG azimuth (+16.2(10.5-21.9)°; p<0.0001), with a significant random effect between families (+20.8 (8.2-33.5)°; p=0.001). SAI QRST was larger in women with CVD as compared with CVD-free women or men (+15.1 (3.8-26.4) mV*ms; p=0.009). Men with CVD had a smaller T area (by 5.1 (95% CI 1.2 to 9.0) mV*ms) and T peak magnitude (by 44 (95%CI 16 to 71) µV) than CVD-free men. T vectors pointed more posteriorly in women as compared with men (peak T azimuth + 17.2(8.9-25.6)°; p<0.0001), with larger sex differences in T azimuth in some families by +26.3(7.4-45.3)°; p=0.006., Conclusions: There are sex differences in the electrical signature of CVD in African-American men and women. There is a significant effect of unmeasured genetic and environmental factors on cardiac repolarisation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Almost half of African American (AA) men and women have cardiovascular disease (CVD). Detection of prevalent CVD in community settings would facilitate secondary prevention of CVD. We sought to develop a tool for automated CVD detection., Methods and Results: Participants from the Jackson Heart Study (JHS) with analysable electrocardiograms (ECGs) ( n =3679; age, 6212 years; 36% men) were included. Vectorcardiographic (VCG) metrics QRS, T, and spatial ventricular gradient vectors magnitude and direction, and traditional ECG metrics were measured on 12-lead ECG. Random forests, convolutional neural network (CNN), lasso, adaptive lasso, plugin lasso, elastic net, ridge, and logistic regression models were developed in 80% and validated in 20% samples. We compared models with demographic, clinical, and VCG input (43 predictors) and those after the addition of ECG metrics (695 predictors). Prevalent CVD was diagnosed in 411 out of 3679 participants (11.2%). Machine learning models detected CVD with the area under the receiver operator curve (ROC AUC) 0.690.74. There was no difference in CVD detection accuracy between models with VCG and VCG + ECG input. Models with VCG input were better calibrated than models with ECG input. Plugin-based lasso model consisting of only two predictors (age and peak QRS-T angle) detected CVD with AUC 0.687 [95% confidence interval (CI) 0.6250.749], which was similar ( P =0.394) to the CNN (0.660; 95% CI 0.5970.722) and better ( P <0.0001) than random forests (0.512; 95% CI 0.4930.530)., Conclusions: Simple model (age and QRS-T angle) can be used for prevalent CVD detection in limited-resources community settings, which opens an avenue for secondary prevention of CVD in underserved communities., (The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Minimally invasive nerve decompression for operative management of Morton's neuroma has been shown to be an effective alternative to neurectomy; however, little is known about postoperative outcomes. In this retrospective case series, we reviewed 27 procedures in 25 patients who underwent minimally invasive nerve decompression as primary surgical management for Morton's neuroma. Most subjects (22, or 88%) had 12 or more months of health plan enrollment postoperatively; 3 (12%) had 4 to 7 months of enrollment after the procedure. Postoperative patient satisfaction, complications and the need for a follow-up neurectomy were ascertained from medical record review. Additionally, demographic and clinical data were extracted from electronic sources. Patient satisfaction was unknown for 5 (18.5%) of the 27 procedures. Among the 22 (81.5%) procedures for which there were valid patient satisfaction data, patient satisfaction was excellent for 11 (50%); good for 2 (9.1%), and poor for 9 (40.9%). During the follow-up period, 5 (18.5%) patients required an open neurectomy. Among the 6 (22.2%) patients who presented without a Mulder's sign on physical exam preoperatively, 83% reported excellent results. Minimally invasive nerve decompression may not be as effective as previously seen; however, it may be indicated in patients presenting with absence of a Mulder's sign, a physically small or nascent neuroma., (Copyright © 2020 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

In an attempt at limb salvage for patients with peripheral arterial disease, revascularization is often performed prior to pedal amputation. The purpose of this study was to evaluate the association between proximal arterial lesions, based on Trans-Atlantic Inter-Society Consensus aortoiliac, femoropopliteal, and infrapopliteal classifications, and healing pedal amputations post endovascular revascularization. Patients with revascularization up to 90 days prior to pedal amputation with a minimum of 12 months postoperative follow-up were included. Each level of proximal disease was subdivided into Trans-Atlantic Inter-Society Consensus classifications A through D, which range in severity from a single short stenosis or occlusion to more complex stenoses and chronic total occlusion. For comparison, we categorized A and/or B lesions into Group 1 and C and/or D lesions into Group 2. The frequency of proximal lesions was recorded as either isolated, bi-level, or multilevel disease. Chi-square and Fisher's exact tests were used to compare categorical variables. Of the 310 patients, there were a total of 68 aortoiliac, 256 femoropopliteal, and 172 infrapopliteal lesions; 140 patients had isolated lesions, 154 had bi-level disease, and 16 had multilevel disease. Although not statistically significant, patients in Group 1 (A and/or B lesions) had higher proportion of failed amputation compared to Group 2 (C and/or D lesions) in either aortoiliac (84.4% vs 15.6%, p = .17), femoropopliteal (61.2% vs 38.8%, p = .72), or infrapopliteal (57.3% vs 42.7%, p = .44). Bi-level disease showed a higher proportion of failure (50.6%) compared to isolated lesions (43.8%) and multilevel disease (5.6%), (p = .86). To our knowledge, this is the first study to evaluate the association between Trans-Atlantic Inter-Society Consensus arterial lesions and incisional healing of pedal amputations. Despite our belief, there was no correlation between patients with simple, isolated lesions compared to either complex arterial lesions or multilevel disease in healing pedal amputations., (Copyright © 2020 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

There has been a growing trend toward endovascular intervention to improve peripheral flow in patients with peripheral arterial disease. To date, there is no clear consensus regarding timing of lower-extremity amputations after revascularization. The purpose of this study was to evaluate the effects of timing between endovascular intervention and minor lower-extremity amputations and its influence on wound healing and limb loss within 1 year. A secondary purpose was to evaluate the impact of restoring in-line flow on healing rates. A total of 310 patients who underwent endovascular intervention and a minor lower-extremity amputation within 90 days were included in the study. Healing rates were defined as optimal, delayed, or failure. There was a statistically significant difference between patients with optimal healing to delayed healing and amputation ≥30 days after endovascular intervention (p = .037). We found no difference in healing rates in regard to amputation timing when examining patients who ultimately healed versus patients who failed to heal (p = .6717). Absence of in-line flow (p = .0177), male sex (p = .0090) and diabetes mellitus (p = .0076) were statistically significant factors for failing to heal. Presence of infection (p ≤ .0001) and wound dehiscence (p ≤ .001) were also associated with a failure to heal. End-stage renal disease trended toward significance for failing to heal (p = .065). Amputation-free survival at 1 year after endovascular intervention and pedal amputation was 76.8% (n = 238). Our findings suggest that in the absence of infection, performing minor lower-extremity amputations 15 to 60 days after endovascular intervention may allow for improved healing. Absence of in-line flow, male sex, diabetes mellitus, postoperative infection, and wound dehiscence are significant factors for failure., (Copyright © 2020 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) show overlap in their clinical features. We performed an analysis of relapses with the aim of determining differences between the two conditions. Cases of NMOSD and age- and sex-matched MS controls were collected from across Australia and New Zealand. Demographic and clinical information, including relapse histories, were recorded using a standard questionnaire. There were 75 cases of NMOSD and 101 MS controls. There were 328 relapses in the NMOSD cases and 375 in MS controls. Spinal cord and optic neuritis attacks were the most common relapses in both NMOSD and MS. Optic neuritis ( p < 0.001) and area postrema relapses ( P = 0.002) were more common in NMOSD and other brainstem attacks were more common in MS ( p < 0.001). Prior to age 30 years, attacks of optic neuritis were more common in NMOSD than transverse myelitis. After 30 this pattern was reversed. Relapses in NMOSD were more likely to be treated with acute immunotherapies and were less likely to recover completely. Analysis by month of relapse in NMOSD showed a trend toward reduced risk of relapse in February to April compared to a peak in November to January ( P = 0.065). Optic neuritis and transverse myelitis are the most common types of relapse in NMOSD and MS. Optic neuritis tends to occur more frequently in NMOSD prior to the age of 30, with transverse myelitis being more common thereafter. Relapses in NMOSD were more severe. A seasonal bias for relapses in spring-summer may exist in NMOSD., (Copyright © 2020 Khalilidehkordi, Clarke, Arnett, Bukhari, Jimenez Sanchez, O'Gorman, Sun, Prain, Woodhall, Silvestrini, Bundell, Abernethy, Bhuta, Blum, Boggild, Boundy, Brew, Brown, Brownlee, Butzkueven, Carroll, Chen, Coulthard, Dale, Das, Fabis-Pedrini, Fulcher, Gillis, Hawke, Heard, Henderson, Heshmat, Hodgkinson, Kilpatrick, King, Kneebone, Kornberg, Lechner-Scott, Lin, Lynch, Macdonell, Mason, McCombe, Pereira, Pollard, Ramanathan, Reddel, Shaw, Spies, Stankovich, Sutton, Vucic, Walsh, Wong, Yiu, Barnett, Kermode, Marriott, Parratt, Slee, Taylor, Willoughby, Brilot, Vincent, Waters and Broadley.)

Neuromyelitis optica spectrum disorders (NMOSD) are an inflammation of the central nervous system associated with autoantibodies to aquaporin-4. We have undertaken a clinic-based survey of NMOSD in the Australia and New Zealand populations with the aim of characterising the clinical features and establishing the value of recently revised diagnostic criteria. Cases of possible NMOSD and age and sex-matched controls with multiple sclerosis (MS) were referred from centres across Australia and New Zealand. Cases were classified as NMOSD if they met the 2015 IPND criteria and remained as suspected NMOSD if they did not. Clinical and paraclinical data were compared across the three groups. NMOSD was confirmed in 75 cases and 89 had suspected NMOSD. There were 101 controls with MS. Age at onset, relapse rates and EDSS scores were significantly higher in NMOSD than in MS. Lesions and symptoms referable to the optic nerve were more common in NMOSD whereas brainstem, cerebellar and cerebral lesions were more common in MS. Longitudinally extensive spinal cord lesions were seen in 48/71 (68%) of cases with NMOSD. Elevations of CSF, white cell count and protein were more common in NMOSD. We have confirmed a clinical pattern of NMOSD that has been seen in several geographical regions. We have demonstrated the clinical utility of the current diagnostic criteria. Distinct patterns of disease are evident in NMOSD and MS, but there remains a large number of patients with NMOSD-like features who do not meet the current diagnostic criteria for NMOSD and remain a diagnostic challenge.

Bisphosphonates (BP) are used to treat osteoporosis, although rare atypical femur fractures have occurred with long-term exposure, especially among Asians. Metatarsal fractures have also been reported with atypical femur fracture. We examined the epidemiology of metatarsal fractures among 48,390 females aged ≥50 years who initiated oral BP and were followed for a median 7.7 years, including 68 females who experienced an atypical femur fracture. Incident metatarsal fractures after BP initiation were identified by clinical diagnoses and validated by record review. The association of BP, clinical risk factors, race/ethnicity, and metatarsal fracture was examined by using Cox proportional hazard analyses. Among 1123 females with incident metatarsal fracture, 61.0% had an isolated fifth metatarsal fracture. The incidence of metatarsal fracture was 312 per 100,000 person-years of follow-up and was substantially lower for Asians. The adjusted relative rate for metatarsal fractures was 0.5 (95% confidence interval 0.4 to 0.6) for Asians compared with whites. Younger age, prior fracture, other risk factors, and current BP were associated with an increased relative rate of metatarsal fracture, but BP duration was not. Females with atypical femur fracture were not more likely to experience metatarsal fracture (2.9% versus 2.3%, p = .7), but only 68 females had an atypical fracture and stress fracture of the metatarsals was not examined. Except for age, the demographic profile for metatarsal fracture after initiating BP was similar to that for osteoporotic fracture, with Asians at a much lower risk. Although metatarsal fractures were not associated with BP duration or atypical femur fracture, the subset of metatarsal stress fractures was not specifically examined., (Copyright © 2019 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Conduction block is a pathognomonic feature of immune-mediated neuropathies. The aim of this study was to advance understanding of pathophysiology and conduction block in chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN)., Methods: A multimodal approach was used, incorporating clinical phenotyping, neurophysiology, immunohistochemistry and structural assessments., Results: Of 49 CIDP and 14 MMN patients, 25% and 79% had median nerve forearm block, respectively. Clinical scores were similar in CIDP patients with and without block. CIDP patients with median nerve block demonstrated markedly elevated thresholds and greater threshold changes in threshold electrotonus, whilst those without did not differ from healthy controls in electrotonus parameters. In contrast, MMN patients exhibited marked increases in superexcitability. Nerve size was similar in both CIDP groups at the site of axonal excitability. However, CIDP patients with block demonstrated more frequent paranodal serum binding to teased rat nerve fibres. In keeping with these findings, mathematical modelling of nerve excitability recordings in CIDP patients with block support the role of paranodal dysfunction and enhanced leakage of current between the node and internode. In contrast, changes in MMN probably resulted from a reduction in ion channel density along axons., Conclusions: The underlying pathologies in CIDP and MMN are distinct. Conduction block in CIDP is associated with paranodal dysfunction which may be antibody-mediated in a subset of patients. In contrast, MMN is characterized by channel dysfunction downstream from the site of block., (© 2019 EAN.)

Objective: To improve understanding of disease pathophysiology in anti-myelin-associated glycoprotein (anti-MAG) neuropathy to guide further treatment approaches., Methods: Anti-MAG neuropathy patients underwent clinical assessments, nerve conduction and excitability studies, and ultrasound assessment., Results: Patients demonstrated a distinctive axonal excitability profile characterised by a reduction in superexcitability [MAG: -14.2 ± 1.6% vs healthy controls (HC): -21.8 ± 1.2%; p < 0.01] without alterations in most other excitability parameters. Mathematical modelling of nerve excitability recordings suggested that changes in axonal function could be explained by a 72.5% increase in juxtaparanodal fast potassium channel activation and an accompanying hyperpolarization of resting membrane potential (by 0.3 mV) resulting in a 94.2% reduction in discrepancy between anti-MAG data and the healthy control model. Superexcitability changes correlated strongly with clinical and neurophysiological parameters. Furthermore, structural assessments demonstrated a proximal pattern of nerve enlargement (C6 nerve root cross-sectional area: 15.9 ± 8.1 mm 2 vs HC: 9.1 ± 2.3 mm 2 ; p < 0.05)., Conclusions: The imaging and neurophysiological results support the pathogenicity of anti-MAG IgM. Widening between adjacent loops of paranodal myelin due to antibodies would expand the pathway from the node to the juxtaparanode, increasing activation of juxtaparanodal fast potassium channels, thereby impairing saltatory conduction., Significance: Potassium channel blockers may prove beneficial in restoring conduction closer to its normal state and improving nerve function in anti-MAG neuropathy., (Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Patients requiring a nontraumatic transmetatarsal amputation (TMA) typically have multiple comorbidities that place them at high risk of postoperative complications and additional surgery. The present study identified the demographic, clinical, and surgical risk factors that predict complications after a nontraumatic TMA, including the incidence of 3-year mortality, proximal limb amputation, and lack of healing. The electronic medical records of patients who had undergone TMA within a Kaiser Permanente Northern California facility from March 2007 to January 2012 (n = 375) were reviewed. We used bivariate and multivariate analyses to examine the variations in the rates of TMA complications according to sex, age, race, and comorbid conditions, including nonpalpable pedal pulses, end-stage renal disease, coronary artery disease, hypertension, smoking status, and preoperative albumin <3.5 mg/dL. After a nontraumatic TMA, 136 (36.3%) patients had died within 3 years, 138 (36.8%) had required a more proximal limb amputation, and 83 (22.1%) had healed without complications. The patients with nonpalpable pedal pulses had 3 times the odds of requiring a proximal limb amputation (adjusted odds ratio [aOR] 3.07; 95% confidence interval [CI] 1.84 to 5.11), almost twice the odds of dying within 3 years (aOR 1.70; 95% CI 0.98 to 2.93), and >2 times the odds of not healing after the TMA (aOR 2.45; 95% CI 1.40 to 4.31). The patients with end-stage renal disease had 3 times the odds of dying within 3 years (aOR 3.10; 95% CI 1.69 to 5.70). The present findings can help us identify patients with an increased risk of postoperative complications after nontraumatic TMA, including patients with nonpalpable pedal pulses or end-stage renal disease, and suggest the vulnerability of this patient population., (Copyright © 2018 The American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Sensorimotor neuropathy associated with IgG4 antibodies to neurofascin-155 (NF155) was recently described. The clinical phenotype is typically associated with young onset, distal weakness, and in some cases, tremor., Methods: From a consecutive cohort of 55 patients diagnosed with chronic inflammatory demyelinating polyneuropathy, screening for anti-NF155 antibodies was undertaken. Patients underwent clinical assessment, diagnostic neurophysiology, including peripheral axonal excitability studies and nerve ultrasound., Results: Three of 55 chronic inflammatory demyelinating polyneuropathy patients (5%) tested positive for anti-NF155 IgG4. Patients presenting with more severe disease had higher antibody titers. Ultrasound demonstrated diffuse nerve enlargement. Axonal excitability studies were markedly abnormal, with subsequent mathematical modeling of the results supporting disruption of the paranodal seal., Discussion: A broad spectrum of disease severity and treatment response may be observed in anti-NF155 neuropathy. Excitability studies support the pathogenic role of anti-NF155 IgG4 antibodies targeting the paranodal region. Muscle Nerve 57: 848-851, 2018., (© 2017 Wiley Periodicals, Inc.)

Objective: To estimate the degree of axonal loss in patients diagnosed with multifocal motor neuropathy (MMN) using a novel assessment of motor unit numbers and size., Methods: Automated motor unit number estimation using a compound muscle action potential (CMAP) scan was undertaken in median nerves with conduction block. Results were compared with 30 age-matched healthy controls., Results: Compared with healthy controls, MMN patients had fewer motor units (MMN: 33±11vs HC: 93±36 [mean±SD]; p<0.0001) and larger 'size of the largest unit' (MMN: 1.2±0.5mVvs HC: 0.4±0.1mV; p<0.0001), despite having normal distal CMAP amplitudes (MMN: 7.6±1.8mVvs HC: 8.7±2.5mV; p=0.24)., Conclusions: MMN is associated with marked axonal loss which may be masked by striking re-innervation resulting in preservation of distal CMAP amplitudes., Significance: Assessment of motor unit properties should be incorporated into assessment of disease progression in MMN, given that nerve conduction studies are insensitive to motor unit remodelling., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

Background: Left ventricular false tendons (LVFTs) are chord-like structures that traverse the LV cavity and are generally considered to be benign. However, they have been associated with arrhythmias, LV hypertrophy and LV dilation in some small studies. We hypothesize that LVFTs are associated with LV structural and functional changes assessed by echocardiography., Methods: We retrospectively evaluated echocardiographic and clinical parameters of 126 patients identified as having LVFTs within the past 2 years and compared them to 85 age-matched controls without LVFTs., Results: There were no significant differences in age (52 ± 18 versus 54 ± 18 years, P = 0.37), sex (55% versus 59% men, P = 0.49), race (36% versus 23% white, P = 0.07), systolic blood pressure (131 ± 22 versus 132 ± 23mmHg, P = 0.76) or body mass index (BMI, 31 ± 8 versus 29 ± 10kg/m 2 , P = 0.07) between controls and patients with LVFTs, respectively. Patients with LVFTs had more prevalent heart failure (43% versus 21%, P = 0.001). Patients with LVFTs had more LV dilation, were 2.5 times more likely to have moderate-to-severe mitral regurgitation, had more severe diastolic dysfunction and reduced LV systolic function (18% lower) compared with controls (all P < 0.05). After adjustment for covariates, basal and middle LVFT locations were associated with reduced LV systolic function (P < 0.01), and middle LVFTs were associated with LV dilation (P < 0.01)., Conclusions: Our findings suggest that LVFTs may not be benign variants, and basal and middle LVFTs may have more deleterious effects. Further prospective studies should be performed to determine their pathophysiological significance and whether they play a causal role in LV dysfunction., (Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Autoantibodies to nodal/paranodal proteins have been reported in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). To determine the frequency of anti-paranodal antibodies in our cohort of CIDP patients and to validate the presence anti-nodal antibodies in MMN, sera were screened for IgG against human neurofascin 155, contactin-1, neurofascin 186 and gliomedin using ELISA. In CIDP patients, 7% were anti-NF155 IgG 4 positive and 7% were anti-CNTN1 IgG 4 positive. Positive results were confirmed using cell based assays and indirect immunofluorescence on teased nerve fibres. We did not detect IgG autoantibodies against these nodal/paranodal antigens in MMN patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry., Background: NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established., Methods: Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases., Results: NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD., Conclusions: NMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry., Competing Interests: Competing interests: MHB has received honoraria for participation in advisory boards and travel sponsorship from Novartis, BioCSL, Genzyme and Biogen Idec. MBo has received travel sponsorship and honoraria from Sanofi-Genzyme, Teva, Novartis, BiogenIdec and Roche. BJB has received honoraria as a board member for GlaxoSmithKline, Biogen Idec, ViiV Healthcare and Merck Serono, has received speaker honoraria from ViiV Healthcare, Boehringer Ingelheim, Abbott, AbbVie and Biogen Idec, has received travel sponsorship from Abbott and ViiV Healthcare and has received research support funding from EIi Lilly, GlaxoSmithKline, ViiV Healthcare and Merck Serono. SAB has received honoraria for attendance at advisory boards and travel sponsorship from Bayer Schering Pharma, BiogenIdec, Merck Serono, Novartis and Sanofi-Genzyme, has received speaker honoraria from Biogen Idec and Genzyme, is an investigator in clinical trials sponsored by Biogen Idec, Novartis and Genzyme and was the recipient of an unencumbered research grant from Biogen Idec. HB has received honoraria for serving on scientific advisory boards for Biogen Idec, Novartis and Sanofi-Genzyme, has received conference travel sponsorship from Novartis and Biogen Idec, has received honoraria for speaking and acting as Chair at educational events organised by Novartis, Biogen Idec, Medscape and Merck Serono, serves on steering committees for trials conducted by Biogen Idec and Novartis, is chair (honorary) of the MSBase Foundation, which has received research support from Merck Serono, Novartis, Biogen Idec, Genzyme Sanofi and CSL Biopharma and has received research support form Merck Serono. WMC has been the recipient of travel sponsorship from, and provided advice to, Bayer Schering Pharma, BiogenIdec, Novartis, Genzyme, Sanofi-Aventis, BioCSL and Merck Serono. RCD has received research funding from the National Health and Medical Research Council, MS Research Australia, Star Scientific Foundation, Pfizer Neuroscience, Tourette Syndrome Association, University of Sydney and the Petre Foundation and has received honoraria from Biogen Idec and Bristol-Myers Squibb as an invited speaker. MjF-P has received travel sponsorship from Biogen Australia and New Zealand. RH has received honoraria, educational support and clinic funding from Novartis, Biogen Idec, Genzyme and BioCSL. AGK has received scientific consulting fees and/or lecture honoraria from Bayer, BioCSL, BiogenIdec, Genzyme, Merck, Novartis, Sanofi-Aventis and Teva. TJK has received travel sponsorship from Novartis, BioCSL, Novartis, Merck Serono and BiogenIdec, has received speaker honoraria from Biogen Idec, BioCSL, Merck Serono, Teva, Genzyme and Novartis, has received research support from Biogen Idec, Genzyme, GlaxoSmithKline, Bayer Schering Pharma and Merck Serono and has received scientific consulting fees from GlaxoSmithKline China, Biogen Idec and Novartis. JK has received remuneration for advisory board activities and presentations from Bayer Healthcare, Biogen Idec, BioCSL, Genzyme and Novartis. CK has received travel support, honoraria and advisory board payments from Biogen Idec, Bayer,Genzyme, Novartis and Serono. JL-S has received unencumbered funding as well as honoraria for presentations and membership on advisory boards from Sanofi-Aventis, Biogen Idec, Bayer Health Care, CSL, Genzyme, Merck Serono, Novartis Australia and Teva. RALM has received honoraria for attendance at advisory boards and travel sponsorship from Bayer Schering Pharma, Biogen Idec, CSL, Merck Serono, Novartis and Sanofi-Genzyme. MPMa has received travel sponsorship, honoraria, trial payments, research and clinical support from Bayer Schering Pharma, Biogen Idec, BioCSL, Genzyme, Novartis and Sanofi-Aventis Genzyme. DFM has received honoraria for attendance at advisory boards from Biogen Idec and Novartis, and travel sponsorship from Bayer Schering Pharma, Biogen Idec and Sanofi-Genzyme. PAMcC has received honoraria or travel sponsorship from Novartis, Sanofi-Aventis and Biogen Idec. JAP has received travel sponsorship, honoraria for presentations and membership on advisory boards from Biogen Idec and Novartis and Sanofi-Aventis. JDP has received honoraria for seminars or advisory boards from Teva, Biogen, Sanofi-Genzyme, Novartis, Merck, Bayer and research grants or fellowships from Merck, Novartis, Bayer, Biogen, Sanofi-Genzyme and Teva. SWR has received travel sponsorship, honoraria, trial payments, research and clinical support from Aspreva, Baxter, Bayer Schering Pharma, Biogen Idec, BioCSL, Genzyme, Novartis, Sanofi-Aventis Genzyme and Servier, and is a director of Medical Safety Systems Pty Ltd. CPS has received travel sponsorship from Biogen Idec, Novartis and Bayer Schering Pharma. IS has received remuneration for Advisory Board activities from Biogen, CSL and Bayer Schering Pharma and educational activities with Biogen, CSL and travel sponsorship from Biogen, Novartis and Bayer Schering Pharma. MS has received research support from Novartis, Biogen Idec and BioCSL. JSp has received honoraria for lectures and participation in advisory boards, and travel sponsorship from Novartis, BioCSL, Genzyme and Biogen Idec. BVT has received travel sponsorship from Novartis and Bayer Schering Pharma. AV and the University of Oxford hold patents and receive royalties for antibody testing. PW and the University of Oxford hold patents for antibody assays and have received royalties, has received speaker honoraria from Biogen Idec and Euroimmun AG and travel grants from the Guthy-Jackson Charitable Foundation. EW has received honoraria for participation in advisory boards from Biogen Idec and Novartis, travel sponsorship from Biogen Idec, Bayer Schering Pharma and Teva and is an investigator in clinical trials funded by Biogen Idec and Teva. DA, SBh, SBl, KB, MBr, WBr, WBu, CSB, CCM, LC, AC, CD, KD, DF, DG, SHa, APDH, SHe, SHo, SJ-S, AJK, M-WL, CL, CO’G, MPM, CS, RS, JSt, AV, SV, MWa, RJW, RCW, MWo and EMY report no disclosures., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Lower motor neuron (LMN) syndromes typically present with muscle wasting and weakness and may arise from pathology affecting the distal motor nerve up to the level of the anterior horn cell. A variety of hereditary causes are recognised, including spinal muscular atrophy, distal hereditary motor neuropathy and LMN variants of familial motor neuron disease. Recent genetic advances have resulted in the identification of a variety of disease-causing mutations. Immune-mediated disorders, including multifocal motor neuropathy and variants of chronic inflammatory demyelinating polyneuropathy, account for a proportion of LMN presentations and are important to recognise, as effective treatments are available. The present review will outline the spectrum of LMN syndromes that may develop in adulthood and provide a framework for the clinician assessing a patient presenting with predominantly LMN features., Competing Interests: Competing interests: None declared., (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/.)

Various surgical techniques have been reported for the repair of neglected Achilles tendon ruptures, including V-Y advancements, synthetic augmentations, and collagen implants. The use of an Achilles tendon allograft allows bridging of large defects without donor site morbidity, with a relative ease of technique and adequate graft availability. The present retrospective report focused on the outcomes of a series of 14 patients with neglected ruptures treated with an Achilles tendon allograft. Patients were included in the present series if they had ≥12 months of postoperative follow-up data available and the allograft had been used without any adjunctive procedures. Of the 14 patients, 6 were female (43%) and 8 were male (57%), with a mean follow-up period of 16.1 ± 3 (range 12 to 27) months. The mean interval from the initial injury to surgery was 6.9 ± 5 (range 1 to 28) months. The mean intraoperative defect size was 7.0 ± 3 (range 4 to 15) cm. A calcaneal block was used in 2 patients (14%). All patients were able to perform a single heel rise at a mean of 27 ± 11 (range 12 to 37) weeks postoperatively. Weightbearing in normal shoe gear was achieved at a mean of 13.5 ± 3 (range 12 to 17) weeks. Complications included 1 delayed union (7%) of the calcaneal bone block. Repair of the neglected Achilles tendon rupture with an allograft appears to be an acceptable approach, with good overall outcomes and low risk. These results suggest that this method of repair compares favorably with established alternatives., (Copyright © 2016 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Axonal injury is the pathological correlate of fixed disability in the inflammatory demyelinating disorders of the central and peripheral nervous system. The mechanisms that initiate and propagate neurodegeneration in these conditions are poorly understood, and a lack of available neuroprotective and proreparative therapies represent a significant unmet clinical need. In this article, we review new data pertaining to the convergent and divergent immunological, cellular, and molecular mechanisms that underpin neurodegeneration in multiple sclerosis and the chronic inflammatory demyelinating neuropathies that will inform the development of targeted therapies., Recent Findings: New insights have been gained from recognition of the axon as an integral component of the axon-myelin unit, identification of defects in axonal transport, elucidation of mechanisms of Wallerian degeneration and, in the central nervous system, the appreciation of trans-synaptic axonal degeneration, and widespread cortical synaptopathy. Concurrently, specific immune triggers of axonal injury, particularly in the peripheral immune system; and inhibitors of repair and regrowth, have been identified., Summary: Neurodegeneration is a critical determinant of disability in the inflammatory demyelinating diseases of both the central nervous system and peripheral nervous system. Current therapies are restricted to agents that (effectively) treat the inflammatory components of these conditions. Although propagated, and in some instances triggered, by inflammation, axon damage will in future years be treated or prevented with adjuvant, targeted therapies that exploit emerging pathways to neurodegeneration.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an inflammatory neuropathy, classically characterised by a slowly progressive onset and symmetrical, sensorimotor involvement. However, there are many phenotypic variants, suggesting that CIDP may not be a discrete disease entity but rather a spectrum of related conditions. While the abiding theory of CIDP pathogenesis is that cell-mediated and humoral mechanisms act together in an aberrant immune response to cause damage to peripheral nerves, the relative contributions of T cell and autoantibody responses remain largely undefined. In animal models of spontaneous inflammatory neuropathy, T cell responses to defined myelin antigens are responsible. In other human inflammatory neuropathies, there is evidence of antibody responses to Schwann cell, compact myelin or nodal antigens. In this review, the roles of the cellular and humoral immune systems in the pathogenesis of CIDP will be discussed. In time, it is anticipated that delineation of clinical phenotypes and the underlying disease mechanisms might help guide diagnostic and individualised treatment strategies for CIDP., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system with a multifactorial aetiology and highly variable natural history. A growing understanding of the immunopathogenesis of the condition has led to an expanding array of therapies for this previously untreatable disease. While a cure for MS remains elusive, the potential to reduce inflammatory disease activity by preventing relapses and minimising disease progression is achievable. The importance of early treatment in minimising long-term disability is increasingly recognised. Most of the newer, more effective therapies are associated with risks and practical problems that necessitate an active management strategy and continuous vigilance. While the initiation of these therapies is likely to remain the responsibility of neurologists, other specialist physicians and general practitioners will be involved in the identification and management of adverse effects.

Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy are autoimmune disorders of the peripheral nervous system in which autoantibodies are implicated in the disease pathogenesis. Recent work has focused on the nodal regions of the myelinated axon as potential autoantibody targets. Here we screened patient sera for autoantibodies to neurofascin and assessed the pathophysiological relevance of anti-neurofascin antibodies in vivo. Levels of anti-neurofascin antibodies were higher in sera from patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy when compared with those of controls. Anti-neurofascin antibodies exacerbated and prolonged adoptive transfer experimental autoimmune neuritis and caused conduction defects when injected intraneurally., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is a potentially life-changing immune mediated disease of the central nervous system. Until recently, treatment has been largely confined to acute treatment of relapses, symptomatic therapies and rehabilitation. Through persistent efforts of dedicated physicians and scientists around the globe for 160 years, a number of therapies that have an impact on the long term outcome of the disease have emerged over the past 20 years. In this three part series we review the practicalities, benefits and potential hazards of each of the currently available and emerging treatment options for MS. We pay particular attention to ways of abrogating the risks of these therapies and provide advice on the most appropriate indications for using individual therapies. In Part 1 we review the history of the development of MS therapies and its connection with the underlying immunobiology of the disease. The established therapies for MS are reviewed in detail and their current availability and indications in Australia and New Zealand are summarised. We examine the evidence to support their use in the treatment of MS., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

In this third and final part of our review of multiple sclerosis (MS) treatment we look at the practical day-to-day management issues that are likely to influence individual treatment decisions. Whilst efficacy is clearly of considerable importance, tolerability and the potential for adverse effects often play a significant role in informing individual patient decisions. Here we review the issues surrounding switching between therapies, and the evidence to assist guiding the choice of therapy to change to and when to change. We review the current level of evidence with regards to the management of women in their child-bearing years with regards to recommendations about treatment during pregnancy and whilst breast feeding. We provide a summary of recommended pre- and post-treatment monitoring for the available therapies and review the evidence with regards to the value of testing for antibodies which are known to be neutralising for some therapies. We review the occurrence of adverse events, both the more common and troublesome effects and those that are less common but have potentially much more serious outcomes. Ways of mitigating these risks and managing the more troublesome adverse effects are also reviewed. Finally, we make specific recommendations with regards to the treatment of MS. It is an exciting time in the world of MS neurology and the prospects for further advances in coming years are high., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

In Part 2 of this three part review of multiple sclerosis (MS) treatment with a particular focus on the Australian and New Zealand perspective, we review the newer therapies that have recently become available and emerging therapies that have now completed phase III clinical trial programs. We go on to compare the relative efficacies of these newer and emerging therapies alongside the existing therapies. The effectiveness of β-interferon in the treatment of different stages and the different disease courses of MS is critically reviewed with the conclusion that the absolute level of response in term of annualised relapse rates (where relapses occur) and MRI activity are similar, but are disappointing in terms of sustained disability progression for progressive forms of the disease. Finally we review the controversial area of combination therapy for MS. Whilst it remains the case that we have no cure or means of preventing MS, we do have a range of effective therapies that when used appropriately and early in the disease course can have a significant impact on short term and longer term outcomes., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)