Novel biomechanical test method for cancellous bone screws and screw augmentation with cement.

It is often difficult to achieve adequate screw fixation for plate constructs in fractures with poor quality bone or in metaphyseal bone with extensive bone loss or comminution[7][17]. Furthermore, rescuing or augmenting failed screw fixation in inadequate bone with various cement products has yielded mixed results when tested with pure axial pullout loading[20][21]. In most cases, plate/screw constructs experience both vertical (translational) and horizontal (pullout) forces during physiologic loading[17][20][21]. The increased use of locked screws in plate constructs has also changed the loading patterns of bone screws. For this study, a novel “toggle-out” testing method was developed to more realistically simulate in-vivo loading of screw-plate constructs. Our objective was to compare the fixation of locked and non-locked screws in simulated cancellous bone of three different densities and to determine the effectiveness of augmentation of the screw fixation using either PMMA or a resorbable Calcium Phosphate cement in both stripped and oversized screw holes. Polyurethane foam blocks of 12.5, 20, and 30 lb/ft3 densities representing ostoporotic, normal, and high density cancellous bone respectively (Sawbones, Pacific Research Laboratories, Vashon Island, WA) were used as the bone surrogate for this study. Holes were drilled into the blocks perpendicular to a single face for placement of screws. All screws tested were 4 mm diameter, 32, 34, or 36 mm length stainless steel cancellous bone screws (Stryker, Mahwah, NJ). The holes were either 2.5 mm diameter pilot holes, 4.0 mm diameter (to simulate a stripped screw hole), or 12 mm diameter (bone loss / void). In the 4 mm stripped holes and the12 mm holes, various cements were used to augment the screw fixation. The cements used were PMMA (Simplex, Stryker) and Calcium Phosphate Cement (Trabexus, Vivorté). After placement of the screws or after the cement had set for 24 hours, the blocks were mounted on a load frame (MTS Corp) for cyclic testing. The load fixture allowed screws to be configured either as locked screws or non-locked screws with respect to the plate. Along with cyclic transverse loading, a constant axial pullout force of 20 N was applied to each screw during testing. Cyclic “toggle” loading was applied for 1000 cycles at each of ±25, ±50, ±100, and ±200 N, or until failure by pullout or screw breakage. The average total displacement (positive and negative combined) value for each test was recorded over the last ten load cycles. Under all conditions, the locked screws exhibited significantly less displacement than the non-locked screws (p screws to be set up as locked screws for half of the test conditions. Locking screws exhibited less displacement than non-locking screws across all test samples (P=0.00). This study therefore supports the use of a locking-style cancellous screw in poor quality bone or when cement augmentation of large holes is warranted. The behavior in stripped holes was quite interesting and erratic. The non-locking screws easily pulled out in most cases, but the locking screws were able to survive more cycles. Also, the higher density bone made cement augmentation to prevent pullout more difficult because the cement (especially CaP) does not interdigitate with the high density material. Cement augmentation of large defects and stripped holes in poor quality bone has the potential to be successful regardless of the type of cement used because locking screws were significantly more stable than non-locking screws

Polygenic risk for Alzheimer's disease shapes hippocampal scene-selectivity

Preclinical models of Alzheimer’s disease (AD) suggest APOE modulates brain function in structures vulnerable to AD pathophysiology. However, genome-wide association studies now demonstrate that AD risk is shaped by a broader polygenic architecture, estimated via polygenic risk scoring (AD-PRS). Despite this breakthrough, the effect of AD-PRS on brain function in young individuals remains unknown. In a large sample (N = 608) of young, asymptomatic individuals, we measure the impact of both (i) APOE and (ii) AD-PRS on a vulnerable cortico-limbic scene-processing network heavily implicated in AD pathophysiology. Integrity of this network, which includes the hippocampus (HC), is fundamental for maintaining cognitive function during ageing. We show that AD-PRS, not APOE, selectively influences activity within the HC in response to scenes, while other perceptual nodes remained intact. This work highlights the impact of polygenic contributions to brain function beyond APOE, which could aid potential therapeutic/interventional strategies in the detection and prevention of AD

Clinical Rotation Handbook Promotes Orthopaedic Resident Wellness: A Quality Improvement Study

Introduction. Transitioning from one clinical rotation to the next may be particularly stressful for orthopaedic residents attempting to navigate new work environments with new faculty mentors and new patients. The purpose of this quality improvement (QI) project was to determine if resident stress could be improved by using a handbook to disseminate key rotation-specific data during quarterly rotation transition periods. Methods. A comprehensive electronic handbook was created by residents to describe each rotation in our orthopaedic training program in terms of: (1) faculty and staff contact data, (2) daily clinic and surgery schedules, (3) resident responsibilities and faculty expectations, and (4) key resources and documents. At rotation transition, a session in the academic schedule was dedicated for outgoing residents to update the handbook and to sign-out to incoming residents. Pre- and post-handbook questionnaires were administered to assess resident perceptions of stress or anxiety, preparedness, and confidence before commencing the new rotation. Nonparametric data derived from the surveys were analyzed using the sign test choosing p < 0.05 for a two-tailed test as the level of statistical significance. Results. Most residents perceived improvements in stress/anxiety, preparedness, and confidence understanding rotation expectations after the handbook was implemented. Changes in these three outcome parameters were statistically significant. Conclusions. This rotation transition QI initiative consisting of a resident-authored, rotation-specific electronic handbook and dedicated verbal sign-out session enhanced resident wellness by decreasing stress, increasing preparedness, and improving confidence among residents starting a new rotation. Similar online resources may be useful for trainees in other specialties

Concert recording 2022-04-02b

[Track 1]. Act 1

Concert recording 2022-04-02b

[Track 1]. Act 1

Development and validation of a short form psychometric tool assessing the caregiving Challenge of Living with Cystic Fibrosis (CLCF-SF) in a child.

Caring for a child with cystic fibrosis (CF) is a rigorous daily commitment for caregivers and treatment burden is a major concern. We aimed to develop and validate a short form version of a 46-item tool assessing the Challenge of Living with Cystic Fibrosis (CLCF) for clinical or research use. A novel genetic algorithm based on 'evolving' a subset of items from a pre-specified set of criteria, was applied to optimise the tool, using data from 135 families. Internal reliability and validity were assessed; the latter compared scores to validated tests of parental well-being, markers of treatment burden, and disease severity. The 15-item CLCF-SF demonstrated very good internal consistency [Cronbach's alpha 0.82 (95%CI 0.78-0.87)]. Scores for convergent validity correlated with the Beck Depression Inventory (Rho = 0.48), State Trait Anxiety Inventory (STAI-State, Rho = 0.41; STAI-Trait, Rho = 0.43), Cystic Fibrosis Questionnaire-Revised, lung function (Rho = -0.37), caregiver treatment management (  = 0.48) and child treatment management (  = 0.45), and discriminated between unwell and well children with CF (Mean Difference 5.5, 95%CI 2.5-8.5,  < 0.001), and recent or no hospital admission (MD 3.6, 95%CI 0.25-6.95,  = 0.039). The CLCF-SF provides a robust 15-item tool for assessing the challenge of living with a child with CF

Fecal Pharmacokinetics and Gut Microbiome Effects of oral Omadacycline Versus Vancomycin in Healthy Volunteers

BACKGROUND: Clostridioides difficile infection (CDI) is a common healthcare-associated infection with limited treatment options. Omadacycline, an aminomethylcycline tetracycline, has potent in vitro activity against C difficile and a low propensity to cause CDI in clinical trials. We aimed to assess fecal pharmacokinetics and gut microbiome effects of oral omadacycline compared to oral vancomycin in healthy adults. METHODS: This was a phase 1, nonblinded, randomized clinical trial conducted in healthy volunteers aged 18-40 years. Subjects received a 10-day course of omadacycline or vancomycin. Stool samples were collected at baseline, daily during therapy, and at follow-up visits. Omadacycline and vancomycin stool concentrations were assessed, and microbiome changes were compared. RESULTS: Sixteen healthy volunteers with a mean age of 26 (standard deviation [SD], 5) years were enrolled; 62.5% were male, and participants\u27 mean body mass index was 23.5 (SD, 4.0) kg/m2. Omadacycline was well tolerated with no safety signal differences between the 2 antibiotics. A rapid initial increase in fecal concentrations of omadacycline was observed compared to vancomycin, with maximum concentrations achieved within 48 hours. A significant difference in alpha diversity was observed following therapy in both the omadacycline and vancomycin groups (P \u3c .05). Bacterial abundance and beta diversity analysis showed differing microbiome changes in subjects who received omadacycline versus vancomycin. CONCLUSIONS: Subjects given omadacycline had high fecal concentrations with a distinct microbiome profile compared to vancomycin. CLINICAL TRIALS REGISTRATION: NCT06030219

Alzheimer's genetic risk effects on cerebral blood flow are spatially consistent and proximal to gene expression across the lifespan

Cerebrovascular dysregulation is a hallmark feature of Alzheimer’s disease (AD), where alterations in cerebral blood flow (CBF) are observed decades prior to symptom onset. Genome-wide association studies (GWAS) show that AD has a polygenic aetiology, providing a tool for studying AD susceptibility across the lifespan. Here, we ascertain whether AD genetic risk effects on CBF previously observed (Chandler et al., 2019) remain consistent across the lifespan. We further provide a causal mechanism to AD genetic risk scores (AD-GRS) effects by establishing spatial convergence between AD-GRS associated regional reductions in CBF and mRNA expression of the proximal AD transcripts using independent data from the Allen Brain Atlas. We analysed grey matter (GM) CBF in a young cohort (N=75; aged 18-35) and an older cohort (N=90; aged 55-85). Critically, we observed that AD-GRS was negatively associated with whole brain GM CBF in the older cohort (standardised β −0.38 [−0.68 – −0.09], P = 0.012), consistent with our prior observation in younger healthy adults (Chandler et al., 2019). We then demonstrate that the regional impact of AD-GRS on GM CBF was spatially consistent across the younger and older samples (r = 0.233, P = 0.035). Finally, we show that CBF across the cortex was related to the regional expression of the genes proximal to SNP’s used to estimate AD-GRS in both younger and older cohorts (ZTWO-TAILED = −1.99, P= 0.047; ZTWO-TAILED = −2.153 P = 0.032, respectively). These observations collectively demonstrate that AD risk alleles have a negative influence on brain vascular function and likely contribute to cerebrovascular changes preceding the onset of clinical symptoms, potentially driven by regional expression of proximal AD risk genes across the brain. Our observations suggest that reduced CBF is an early antecedent of AD and a key modifiable target for therapeutic intervention in individuals with a higher cumulative genetic risk for AD. This study will further enable identification of key molecular processes that underpin AD genetic risk related reductions in CBF that could be targeted decades prior to the onset of neurodegeneration

A morphometric comparison of the Namib and southwest Kalahari dunefields using ASTER GDEM data

The increased availability of digital elevation models and satellite image data enable testing of morphometric relationships between sand dune variables (dune height, spacing and equivalent sand thickness), which were originally established using limited field survey data. These long-established geomorphological hypotheses can now be tested against very much larger samples than were possible when available data were limited to what could be collected by field surveys alone. This project uses ASTER global digital elevation model (GDEM) data to compare morphometric relationships between sand dune variables in the southwest Kalahari dunefield to those of the Namib sand sea, to test whether the relationships found in an active sand sea (Namib) also hold for the fixed dune system of the nearby southwest Kalahari. The data show significant morphometric differences between the simple linear dunes of the Namib sand sea and the southwest Kalahari; the latter do not show the expected positive relationship between dune height and spacing. The southwest Kalahari dunes show a similar range of dune spacings, but they are less tall, on average, than the Namib sand sea dunes. There is a clear spatial pattern to these morphometric data; the tallest and most closely spaced dunes are towards the southeast of the Kalahari dunefield; and this is where the highest values of equivalent sand thickness result. We consider the possible reasons for the observed differences and highlight the need for more studies comparing sand seas and dunefields from different environmental settings