TDP-43 proteinopathies: pathological identification of brain regions differentiating clinical phenotypes.

The pathological sequestration of TAR DNA-binding protein 43 (TDP-43, encoded by TARDBP) into cytoplasmic pathological inclusions characterizes the distinct clinical syndromes of amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia, while also co-occurring in a proportion of patients with Alzheimer's disease, suggesting that the regional concentration of TDP-43 pathology has most relevance to specific clinical phenotypes. This has been reflected in the three different pathological staging schemes for TDP-43 pathology in these different clinical syndromes, with none of these staging schemes including a preclinical phase similar to that which has proven beneficial in other neurodegenerative diseases. To apply each of these three staging schemes for TDP-43 pathology, the clinical phenotype must be known undermining the potential predictive value of the pathological examination. The present study set out to test whether a more unified approach could accurately predict clinical phenotypes based solely on the regional presence and severity of TDP-43 pathology. The selection of brain regions of interest was based on key regions routinely sampled for neuropathological assessment under current consensus criteria that have also been used in the three TDP-43 staging schemes. The severity of TDP-43 pathology in these regions of interest was assessed in four clinicopathological phenotypes: amyotrophic lateral sclerosis (n = 27, 47-78 years, 15 males), behavioural variant frontotemporal dementia (n = 15, 49-82 years, seven males), Alzheimer's disease (n = 26, 51-90 years, 11 males) and cognitively normal elderly individuals (n = 17, 80-103 years, nine males). Our results demonstrate that the presence of TDP-43 in the hypoglossal nucleus discriminates patients with amyotrophic lateral sclerosis with an accuracy of 98%. The severity of TDP-43 deposited in the anterior cingulate cortex identifies patients with behavioural variant frontotemporal dementia with an accuracy of 99%. This identification of regional pathology associated with distinct clinical phenotypes suggests key regions on which probabilistic pathological criteria, similar to those currently available for Alzheimer's disease and dementia with Lewy bodies, can be developed for TDP-43 proteinopathies. We propose and validate a simplified probabilistic statement that involves grading the presence of TDP-43 in the hypoglossal nucleus and the severity of TDP-43 in the anterior cingulate for the pathological identification of TDP-43 proteinopathy cases with clinical amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia.

Imageless navigation system (Naviswiss) provides accurate component position in total hip arthroplasty with lateral decubitus position for end-stage hip osteoarthritis: a prospective cohort study with CT-validation.

AIMS: The Naviswiss system (Naviswiss AG, Brugg, Switzerland) is a handheld imageless navigation device used to improve the accuracy of implant positioning in total hip arthroplasty (THA). However, clinical data for leg length discrepancy and femoral offset is lacking, and the validity of the system has not been reported for patients undergoing THA in the lateral decubitus position. This study aimed to report the accuracy of the device in this patient population. METHODS: Patients underwent THA in the lateral decubitus position performed by a single surgeon. Component position measured by the device intraoperatively was compared to postoperative measurements on computed tomography (CT) scans. Agreement between the navigation system and postoperative measurements was reported for acetabular cup inclination, acetabular cup version, femoral offset, and leg length discrepancy. RESULTS: Thirty-three patients were included in the analysis. The mean difference between intraoperative and postoperative CT measurements was within 2° for angular measurements and 2 mm for leg length. Absolute differences in the two indices were up to 4° and 3 mm. The mean bias was 1°-2° overestimation for cup orientation and up to 2 mm overestimation for leg length change. However, 95% limits of agreement did not exceed absolute thresholds of 10° and 10 mm, especially after correction for bias. One case (3%) was declared intraoperatively for issues with fixation on the greater trochanter. CONCLUSIONS: The accuracy of the Naviswiss system falls within clinically acceptable recommendations for acetabular cup placement, femoral offset, and leg length for total hip arthroplasty with a anterolateral approach in lateral decubitus position. The system could be further improved with regression-based bias correction.

The effect of osteotomy technique (flat-cut vs wedge-cut Weil) on pain relief and complication incidence following surgical treatment for metatarsalgia in a private metropolitan clinic: protocol for a randomised controlled trial.

BACKGROUND: Weil osteotomies are performed to surgically treat metatarsalgia, by shortening the metatarsal via either a single distal oblique cut with translation of the metatarsal head (flat-cut) or through the removal of a slice of bone (wedge-cut). The wedge-cut technique purportedly has functional and mechanical advantages over the flat-cut procedure; however, in vivo data and quality of evidence are currently lacking. This study aims to investigate whether wedge-cut Weil osteotomy compared to traditional flat-cut Weil is associated with increased pain relief and fewer complications up to 12 months postoperatively. METHODS: Patient, surgical and clinical data will be collected for 80 consecutive consenting patients electing to undergo surgical treatment of propulsive metatarsalgia in a randomised control trial, embedded within a clinical registry. The primary outcome is patient-reported pain as assessed by the Foot and Ankle Outcome Score (FAOS) - Pain subscale, and the secondary outcome is the incidence of procedure-specific complications at up to 12 months postoperatively. The groups will be randomised using a central computer-based simple randomisation system, with a 1:1 allocation without blocking and allocation concealment. A mixed-effects analysis of covariance will be used to assess the primary outcome, with confounders factored into the model. A binary logistic regression will be used to assess the secondary outcome in a multivariable model containing the same confounders. DISCUSSION: To the best of the authors' knowledge, the trial will be the first to examine the clinical efficacy of the wedge-cut Weil osteotomy compared to the flat-cut technique with a prospective, randomised control design. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12620001251910. Registered on 23 November 2020.

Patient-reported outcomes of a short hospital stay after total knee replacement in a regional public hospital: a prospective cohort treated 2018-2019.

BACKGROUND: Patient-reported outcomes and satisfaction following short length of stay (LoS) after total knee arthroplasty (TKA) in the Australian regional context remain unexplored. This study reports complications, outcomes and satisfaction of patients discharged from an enhanced recovery protocol (ERP), 6 weeks after TKA in a regional hospital. METHODS: Prospective recruitment occurred between 2018 and 2019. Demographics, intraoperative data, complications and emergency department (ED) presentations were retrieved from hospital records. Complications were graded for severity using a published scale. Knee range of motion (ROM), timed up-and-go (TUG), 6-min walk test (6MWT) and Oxford Knee Scores (OKS) were assessed preoperatively and 6 weeks postoperatively. Patient satisfaction was assessed via questionnaire at the postoperative follow-up. RESULTS: One hundred patients/117 primary TKAs were prospectively included. Median LoS was 2 days (interquartile range 1-3 days) with 74.4% and 88.4% of patients satisfied with their knee and LoS, at 6 weeks respectively. Twenty-seven patients presented to the ED a total of 37 times with complication severity of Grade III or less, and 10 patients were readmitted. Significant improvements in objective and subjective outcomes were observed, however only change in median OKS exceeded the minimal clinically important difference (MCID) threshold. CONCLUSION: An enhanced recovery protocol after TKA in a regional hospital can achieve a median LoS of 2 days without compromising patient-reported outcomes and objective functional measures, whilst maintaining a high level of patient satisfaction with both the surgery and LoS. Further work is required to better optimize management of largely low-grade complications in this patient population.

Towards a Dynamic Model of the Kangaroo Knee for Clinical Insights into Human Knee Pathology and Treatment: Establishing a Static Biomechanical Profile.

There is limited understanding of how patella realignment or patellectomy to surgically manage patellofemoral pain (PFP) affects knee biomechanics. By analysing marsupials like kangaroos that lack an ossified patella, actionable biomimetic insight for the management of end-stage PFP could be gained. This study aimed to provide the foundation of a multi-stage approach, by establishing a static biomechanical profile of the kangaroo stifle that informs the inputs and factors requiring consideration for future dynamic analyses. Volumetric CT and MRI sequences were obtained for four hindlimbs from two Macropus giganteus specimens, from which three-dimensional models of the stifles were created. Two limbs were dissected to visualise the insertion points, origins and lines of action of the quadriceps muscles and the knee extensor mechanism. Static measurements were obtained from the three-dimensional models to establish the biomechanical profile. The results confirmed structural differences in the kangaroo stifle with lack of an ossified patella, a prominent tuberosity and a shorter femur, which functionally affect the mechanical advantage and the torque-generating capability of the joint. The data reported in this study can be used to inform the inputs and constraints of future comparative analyses from which important lessons can be learned for the human knee.

Spread of pathology in amyotrophic lateral sclerosis: assessment of phosphorylated TDP-43 along axonal pathways.

INTRODUCTION: The progression of amyotrophic lateral sclerosis (ALS) through the brain has recently been staged using independent neuropathological and neuroimaging modalities. The two schemes tie into the concept of pathological spread through corticofugal axonal transmission that stems from observation of oligodendrocyte pTDP-43 aggregates along with neuronal inclusions. Here, we aimed to assess evidence of transmission along axonal pathways by looking for pTDP-43 oligodendrocyte pathology in involved white matter tracts, and to present a first validation of the neuropathological staging scheme. pTDP-43 immunohistochemistry was performed in select white matter tracts and grey matter regions from the staging scheme in postmortem-confirmed ALS cases (N = 34). Double-labelling immunofluorescence was performed to confirm co-localisation of pTDP-43 immunoreactivity to oligodendrocytes. RESULTS: While pTDP-43 immunoreactive oligodendrocytes were frequent in the white matter under the motor and sensory cortices, similar assessment of the white matter along the corticospinal tract and in the corpus callosum and cingulum bundle of the same cases revealed no pTDP-43 pathology, questioning the involvement of oligodendrocytes in pathological propagation. The assessment of Betz cell loss revealed that the lack of deep white matter pTDP-43 oligodendrocyte pathology was not due to an absence of motor axons. Assessment of the propagation of pathology to different grey matter regions validated that all cases could be allocated to one of four neuropathological stages, although Stage 4 cases were found to differ significantly in age of onset (~10 years older) and disease duration (shorter duration than Stage 3 and similar to Stage 2). CONCLUSIONS: Four stages of ALS neuropathology can be consistently identified, although evidence of sequential clinical progression requires further assessment. As limited pTDP-43 oligodendrocyte pathology in deep corticospinal and other white matter tracts from the motor cortex was observed, the propagation of pathology between neurons may not involve oligodendrocytes and the interpretation of the changes observed on neuroimaging should be modified accordingly.