Peptide:glycosaminoglycan hybrid hydrogels as an injectable intervention for spinal disc degeneration

Degeneration of the spinal discs is a major cause of back pain. During the degeneration process, there is a loss of glycosaminoglycans (GAGs) from the proteoglycan-rich gel in the disc’s nucleus, which adversely alters biomechanical performance. Current surgical treatments for back pain are highly invasive and have low success rates; there is an urgent need for minimally-invasive approaches that restore the physiological mechanics of the spine. Here we present an injectable peptide:GAG hydrogel that rapidly self-assembles in situ and restores the mechanics of denucleated intervertebral discs. It forms a gel with comparable mechanical properties to the native tissue within seconds to minutes depending on the peptide chosen. Unlike other biomaterials that have been proposed for this purpose, these hybrid hydrogels can be injected through a very narrow 25 G gauge needle, minimising damage to the surrounding soft tissue, and they mimic the ability of the natural tissue to draw in water by incorporating GAGs. Furthermore, the GAGs enhance the gelation kinetics and thermodynamic stability of peptide hydrogels, significantly reducing effusion of injected material from the intervertebral disc (GAG leakage of 8 ± 3% after 24 hrs when peptide present, compared to 39 ± 3% when no peptide present). In an ex vivo model, we demonstrate that the hydrogels can restore the compressive stiffness of denucleated bovine intervertebral discs. Compellingly, this novel biomaterial has the potential to transform the clinical treatment of back pain by resolving current surgical challenges, thus improving patient quality of life

An Economic Study of the Effect of Android Platform Fragmentation on Security Updates

Vendors in the Android ecosystem typically customize their devices by modifying Android Open Source Project (AOSP) code, adding in-house developed proprietary software, and pre-installing third-party applications. However, research has documented how various security problems are associated with this customization process. We develop a model of the Android ecosystem utilizing the concepts of game theory and product differentiation to capture the competition involving two vendors customizing the AOSP platform. We show how the vendors are incentivized to differentiate their products from AOSP and from each other, and how prices are shaped through this differentiation process. We also consider two types of consumers: security-conscious consumers who understand and care about security, and na\"ive consumers who lack the ability to correctly evaluate security properties of vendor-supplied Android products or simply ignore security. It is evident that vendors shirk on security investments in the latter case. Regulators such as the U.S. Federal Trade Commission have sanctioned Android vendors for underinvestment in security, but the exact effects of these sanctions are difficult to disentangle with empirical data. Here, we model the impact of a regulator-imposed fine that incentivizes vendors to match a minimum security standard. Interestingly, we show how product prices will decrease for the same cost of customization in the presence of a fine, or a higher level of regulator-imposed minimum security.Comment: 22nd International Conference on Financial Cryptography and Data Security (FC 2018

Trajectories of childhood body mass index are associated with adolescent sagittal standing posture

Objectives. To identify distinct age-related trajectory classes of body mass index (BMI) z-scores from childhood to adolescence, and to examine the association of these trajectories with measures of standing sagittal spinal alignment at 14 years of age. Methods. Adolescents participating in the Western Australian Pregnancy Cohort (Raine) Study contributed data to the study (n=1 373). Age- and gender-specific z-scores for BMI were obtained from height and weight at the ages of 3, 5, 10 and 14 years. Latent class group analysis was used to identify six distinct trajectory classes of BMI z-score. At the age of 14 years, adolescents were categorised into one of four subgroups of sagittal spinal posture using k-means cluster analysis of photographic measures of lumbar lordosis, thoracic kyphosis and trunk sway. Regression modeling was used to assess the relationship between postural angles and subgroups, and different BMI trajectory classes, adjusting for gender. Results. Six trajectory classes of BMI z-score were estimated: Very Low (4%), Low (24%), Average (34%), Ascending (6%), Moderate High (26%) and Very High (6%). The proportions of postural subgroups at age 14 were; Neutral (29%), Flat (22%), Sway (27%) and Hyperlordotic (22%). BMI trajectory class was strongly associated with postural subgroup, with significantly higher proportions of adolescents in the Very High, High and Ascending BMI trajectory classes displaying a Hyperlordotic or Sway posture than a Neutral posture at age 14. Conclusions. This prospective study provides evidence that childhood obesity, and how it develops, is associated with standing sagittal postural alignment in adolescence

Reduced risk of Barrett’s esophagus in statin users: case–control study and meta-analysis

Background: Use of statins has been associated with a reduced incidence of esophageal adenocarcinoma in population-based studies. However there are few studies examining statin use and the development of Barrett’s esophagus. Aim: The purpose of this study was to examine the association between statin use and the presence of Barrett’s esophagus in patients having their first gastroscopy. Methods: We have performed a case–control study comparing statin use between patients with, and without, an incident diagnosis of non-dysplastic Barrett’s esophagus. Male Barrett’s cases (134) were compared to 268 male age-matched controls in each of two control groups (erosive gastro-esophageal reflux and dyspepsia without significant upper gastrointestinal disease). Risk factor and drug exposure were established using standardised interviews. Logistic regression was used to compare statin exposure and correct for confounding factors. We performed a meta-analysis pooling our results with three other case–control studies. Results: Regular statin use was associated with a significantly lower incidence of Barrett’s esophagus compared to the combined control groups [adjusted OR 0.62 (95 % confidence intervals 0.37–0.93)]. This effect was more marked in combined statin plus aspirin users [adjusted OR 0.43 (95 % CI 0.21–0.89)]. The inverse association between statin or statin plus aspirin use and risk of Barrett’s was significantly greater with longer duration of use. Meta-analysis of pooled data (1098 Barrett’s, 2085 controls) showed that statin use was significantly associated with a reduced risk of Barrett’s esophagus [pooled adjusted OR 0.63 (95 % CI 0.51–0.77)]. Conclusions: Statin use is associated with a reduced incidence of a new diagnosis of Barrett’s esophagus

Hydrodynamic Mixing Tunes the Stiffness of Proteoglycan‐Mimicking Physical Hydrogels

Self‐assembling hydrogels are promising materials for regenerative medicine and tissue engineering. However, designing hydrogels that replicate the 3–4 order of magnitude variation in soft tissue mechanics remains a major challenge. Here hybrid hydrogels are investigated formed from short self‐assembling β‐fibril peptides, and the glycosaminoglycan chondroitin sulfate (CS), chosen to replicate physical aspects of proteoglycans, specifically natural aggrecan, which provides structural mechanics to soft tissues. Varying the peptide:CS compositional ratio (1:2, 1:10, or 1:20) can tune the mechanics of the gel by one to two orders of magnitude. In addition, it is demonstrated that at any fixed composition, the gel shear modulus can be tuned over approximately two orders of magnitude through varying the initial vortex mixing time. This tuneability arises due to changes in the mesoscale structure of the gel network (fibril width, length, and connectivity), giving rise to both shear‐thickening and shear‐thinning behavior. The resulting hydrogels range in shear elastic moduli from 0.14 to 220 kPa, mimicking the mechanical variability in a range of soft tissues. The high degree of discrete tuneability of composition and mechanics in these hydrogels makes them particularly promising for matching the chemical and mechanical requirements of different applications in tissue engineering and regenerative medicine

Comparing Reactogenicity of COVID-19 vaccines: a systematic review and meta-analysis.

OBJECTIVES: A number of vaccines have now been developed against COVID-19. Differences in reactogenicity and safety profiles according to the vaccine technologies employed are becoming apparent from clinical trials. METHODS: Five databases (Medline, EMBASE, Science Citation Index, Cochrane Central Register of Controlled Trials, London School of Hygiene and Tropical Medicine COVID-19 vaccine tracker) were searched for relevant randomised controlled trials between 1 January 2020 and 12 January 2022 according to predetermined criteria with no language limitations. RESULTS: Forty-two datasets were identified, with 20 vaccines using four different technologies (viral vector, inactivated, mRNA and protein sub-unit). Adults and adolescents over 12 years were included. Control groups used saline placebos, adjuvants, and comparator vaccines. The most consistently reported solicited adverse events were fever, fatigue, headache, pain at injection site, redness, and swelling. Both doses of mRNA vaccines, the second dose of protein subunit and the first dose of adenovirus vectored vaccines were the most reactogenic, while the inactivated vaccines were the least reactogenic. CONCLUSIONS: The different COVID-19 vaccines currently available appear to have distinct reactogenicity profiles, dependent on the vaccine technology employed. Awareness of these differences may allow targeted recommendations for specific populations. Greater standardization of methods for adverse event reporting will aid future research in this field

Spin, charge and orbital ordering in ferrimagnetic insulator YBaMn2_2O5_5

The oxygen-deficient (double) perovskite YBaMn$_2$O$_5$, containing corner-linked MnO$_5$ square pyramids, is found to exhibit ferrimagnetic ordering in its ground state. In the present work we report generalized-gradient-corrected, relativistic first-principles full-potential density-functional calculations performed on YBaMn$_2$O$_5$ in the nonmagnetic, ferromagnetic and ferrimagnetic states. The charge, orbital and spin orderings are explained with site-, angular momentum- and orbital-projected density of states, charge-density plots, electronic structure and total energy studies. YBaMn$_2$O$_5$ is found to stabilize in a G-type ferrimagnetic state in accordance with experimental results. The experimentally observed insulating behavior appears only when we include ferrimagnetic ordering in our calculation. We observed significant optical anisotropy in this material originating from the combined effect of ferrimagnetic ordering and crystal field splitting. In order to gain knowledge about the presence of different valence states for Mn in YBaMn$_2$O$_5$ we have calculated $K$-edge x-ray absorption near-edge spectra for the Mn and O atoms. The presence of the different valence states for Mn is clearly established from the x-ray absorption near-edge spectra, hyperfine field parameters and the magnetic properties study. Among the experimentally proposed structures, the recently reported description based on $P$4/$nmm$ is found to represent the stable structure

Implementation of a novel stratified PAthway of CarE for common musculoskeletal (MSK) conditions in primary care: Protocol for a multicentre pragmatic randomised controlled trial (the PACE MSK trial)

Introduction Musculoskeletal (MSK) conditions constitute the highest burden of disease globally, with healthcare services often utilised inappropriately and overburdened. The aim of this trial is to evaluate the effectiveness of a novel clinical PAthway of CarE programme (PACE programme), where care is provided based on people's risk of poor outcome. Methods and analysis Multicentre randomised controlled trial. 716 people with MSK conditions (low back pain, neck pain or knee osteoarthritis) will be recruited in primary care. They will be stratified for risk of a poor outcome (low risk/high risk) using the Short Form Örebro Musculoskeletal Pain Screening Questionnaire (SF-ÖMSPQ) then randomised to usual care (n=358) or the PACE programme (n=358). Participants at low risk in the PACE programme will receive up to 3 sessions of guideline based care from their primary healthcare professional (HCP) supported by a custom designed website (mypainhub.com). Those at high risk will be referred to an allied health MSK specialist who will conduct a comprehensive patient-centred assessment then liaise with the primary HCP to determine further care. Primary outcome (SF 12-item PCS) and secondary outcomes (eg, pain self-efficacy, psychological health) will be collected at baseline, 3, 6 and 12 months. Cost-effectiveness will be measured as cost per quality-Adjusted life-year gained. Health economic analysis will include direct and indirect costs. Analyses will be conducted on an intention-To-Treat basis. Primary and secondary outcomes will be analysed independently, using generalised linear models. Qualitative and mixed-methods studies embedded within the trial will evaluate patient experience, health professional practice and interprofessional collaboration. Ethics and dissemination Ethics approval has been received from the following Human Research Ethics Committees: The University of Sydney (2018/926), The University of Queensland (2019000700/2018/926), University of Melbourne (1954239), Curtin University (HRE2019-0263) and Northern Sydney Local Health District (2019/ETH03632). Dissemination of findings will occur via peer-reviewed publications, conference presentations and social media. Trial registration number ACTRN12619000871145

?2-Microglobulin Amyloid Fibril-Induced Membrane Disruption Is Enhanced by Endosomal Lipids and Acidic pH

Although the molecular mechanisms underlying the pathology of amyloidoses are not well understood, the interaction between amyloid proteins and cell membranes is thought to play a role in several amyloid diseases. Amyloid fibrils of ?2-microglobulin (?2m), associated with dialysis-related amyloidosis (DRA), have been shown to cause disruption of anionic lipid bilayers in vitro. However, the effect of lipid composition and the chemical environment in which ?2m-lipid interactions occur have not been investigated previously. Here we examine membrane damage resulting from the interaction of ?2m monomers and fibrils with lipid bilayers. Using dye release, tryptophan fluorescence quenching and fluorescence confocal microscopy assays we investigate the effect of anionic lipid composition and pH on the susceptibility of liposomes to fibril-induced membrane damage. We show that ?2m fibril-induced membrane disruption is modulated by anionic lipid composition and is enhanced by acidic pH. Most strikingly, the greatest degree of membrane disruption is observed for liposomes containing bis(monoacylglycero)phosphate (BMP) at acidic pH, conditions likely to reflect those encountered in the endocytic pathway. The results suggest that the interaction between ?2m fibrils and membranes of endosomal origin may play a role in the molecular mechanism of ?2m amyloid-associated osteoarticular tissue destruction in DRA