Strategies for fixation of periprosthetic fragility fractures of the neck of femur below a well-functioning hip resurfacing arthroplasty: A case-series.

Introduction: Metal-on-metal Hip Resurfacing (HR) was performed in many young individuals as it conserved bone stock and had low wear rates, before it became less popular due to the detection of Adverse Reactions to Metal Debris. As such, many patients in the community have well-functioning HRs and as they age, the incidence of fragility fractures of the neck of femur around the existing implant is expected to increase. These fractures are amenable to surgical fixation as adequate bone stock remains in the head of the femur and the implants are well fixed. Case-series: We present a series of six cases which were treated by fixation using locked plates (3), dynamic hip screws (2) and cephalo-medullary nail (1). Four cases achieved clinical and radiographic union with good function. One case had a delayed union, though union was finally achieved at 23 months. One case had an early failure necessitating revision to a Total Hip Replacement after 6 weeks. Discussion: We highlight the geometrical principles of placing fixation devices under an HR femoral component. We have also conducted a literature search and present details of all case reports to date. Conclusion: Fragility per-trochanteric fractures under a well-fixed HR with good baseline function are amenable to fixation using a variety of methods including large screw devices that are commonly used in this location. Locked plates including variable angle locking designs should be kept available if needed.

Determinants of intrinsic aminoglycoside resistance in Pseudomonas aeruginosa.

Screening of a transposon insertion mutant library of Pseudomonas aeruginosa for increased susceptibility to paromomycin identified a number of genes whose disruption enhanced susceptibility of this organism to multiple aminoglycosides, including tobramycin, amikacin, and gentamicin. These included genes associated with lipid biosynthesis or metabolism (lptA, faoA), phosphate uptake (pstB), and two-component regulators (amgRS, PA2797-PA2798) and a gene of unknown function (PA0392). Deletion mutants lacking these showed enhanced panaminoglycoside susceptibility that was reversed by the cloned genes, confirming their contribution to intrinsic panaminoglycoside resistance. None of these mutants showed increased aminoglycoside permeation of the cell envelope, indicating that increased susceptibility was not related to enhanced aminoglycoside uptake owing to a reduced envelope barrier function. Several mutants (pstB, faoA, PA0392, amgR) did, however, show increased cytoplasmic membrane depolarization relative to wild type following gentamicin exposure, consistent with the membranes of these mutants being more prone to perturbation, likely by gentamicin-generated mistranslated polypeptides. Mutants lacking any two of these resistance genes in various combinations invariably showed increased aminoglycoside susceptibility relative to single-deletion mutants, confirming their independent contribution to resistance and highlighting the complexity of the intrinsic aminoglycoside resistome in P. aeruginosa. Deletion of these genes also compromised the high-level panaminoglycoside resistance of clinical isolates, emphasizing their important contribution to acquired resistance.

Pathophysiological metabolic changes associated with disease modify the proarrhythmic risk profile of drugs with potential to prolong repolarisation.

BACKGROUND AND PURPOSE: Hydroxychloroquine, chloroquine and azithromycin are three drugs that were proposed to treat coronavirus disease 2019 (COVID-19). While concern already existed around their proarrhythmic potential, there are little data regarding how altered physiological states encountered in patients such as febrile state, electrolyte imbalances or acidosis might change their risk profiles. EXPERIMENTAL APPROACH: Potency of human ether-à-go-go related gene (hERG) block was measured using high-throughput electrophysiology in the presence of variable environmental factors. These potencies informed simulations to predict population risk profiles. Effects on cardiac repolarisation were verified in human induced pluripotent stem cell-derived cardiomyocytes from multiple individuals. KEY RESULTS: Chloroquine and hydroxychloroquine blocked hERG with IC50 of 1.47 ± 0.07 and 3.78 ± 0.17 µM, respectively, indicating proarrhythmic risk at concentrations effective against severe acute respiratory syndrome-coronovirus-2 (SARS-CoV-2) in vitro. Hypokalaemia and hypermagnesaemia increased potency of chloroquine and hydroxychloroquine, indicating increased proarrhythmic risk. Acidosis significantly reduced potency of all drugs, whereas increased temperature decreased potency of chloroquine and hydroxychloroquine against hERG but increased potency for azithromycin. In silico simulations demonstrated that proarrhythmic risk was increased by female sex, hypokalaemia and heart failure and identified specific genetic backgrounds associated with emergence of arrhythmia. CONCLUSION AND IMPLICATIONS: Our study demonstrates how proarrhythmic risk can be exacerbated by metabolic changes and pre-existing disease. More broadly, the study acts as a blueprint for how high-throughput in vitro screening, combined with in silico simulations, can help guide both preclinical screening and clinical management of patients in relation to drugs with potential to prolong repolarisation.

Low-Cost Nonreversible Electronic-Free Wireless pH Sensor for Spoilage Detection in Packaged Meat Products.

Contamination of meat with pathogenic microorganisms can cause severe illnesses and food waste, which has significant negative impacts on both general health and the economy. In many cases, the expiration date is not a good indicator of meat freshness as there is a high risk of contamination during handling throughout the supply chain. Many biomarkers, including color, odor, pH, temperature, and volatile compounds, are used to determine spoilage. Among these, pH presents a simple and effective biomarker directly linked to the overgrowth of bacteria and degradation of the meat tissue. Low-cost methods for wireless pH monitoring are crucial in detecting spoilage on a large commercial scale. Existing technologies are often limited to short-range detection, with the use of batteries and different electronic components that increases both the manufacturing complexity and cost of the final device. To address these shortcomings, we have developed a cost-effective wireless pH sensor, which uses passive resonant frequency (RF) sensing, combined with a pH-responsive polymer that can be placed within packaged meat products and provide a remote assessment of the risk of microbial spoilage throughout the supply chain. The sensor tag consists of a sensing resonator coated with a pH-sensitive material and a passivated reference resonator operating in a differential frequency configuration. Upon exposure to elevated pH levels >6.8, the coating on the sensing resonator dissolves, which in turn results in a distinct change in the resonant frequency with respect to the reference resonator. Systematic theoretical and experimental results at different pH levels demonstrated that a 20% shift in resonant frequency demarcates the point for spoilage detection. As a proof of concept, the performance of the sensor in remotely detecting the risk of food spoilage was validated in packaged poultry over 10 days. The sensor fabrication process takes advantage of recent developments in the scalable manufacturing of flexible, low-cost devices, including selective laser etching of metalized plastic films and doctor-blade coating of stimuli-responsive polymer films. Furthermore, the biocompatibility of all the materials used in the sensor was confirmed with human intestinal cells (HCT-8 cells).

Ex Vivo Assessment of Different Oral Anticoagulant Regimens on Pump Thrombosis in a HeartWare Ventricular Assist Device.

BACKGROUND: In light of decreased intracranial hemorrhage with direct oral anticoagulants and concerns about their safety in continuous flow left ventricular assist devices, we conducted an ex vivo study of thrombus formation using multiple anticoagulation agents. METHODS: A continuous flow left ventricular assist device (HeartWare ventricular assist device) hemocompatibility loop was run using human blood under 7 conditions: control (no anticoagulation or antiplatelet); in vitro addition of aspirin; in vitro addition of apixaban at low dose (equivalent 2.5 mg twice daily); addition of apixaban at high dose (equivalent 5 mg twice daily); patients on warfarin; patients on apixaban (5 mg twice daily); and patients on dabigatran (150 mg twice daily). The primary outcome was time to formation of intrapump thrombosis. Secondary outcomes were reduction in clotting times over 1 hour, hemolysis, reduced platelet aggregation, and von Willebrand activity. RESULTS: Twenty-one runs were completed. Times to thrombosis in median (interquartile range) were control, 131 (127-134.5); in vitro aspirin, 124 (114.5-137); and patients on dabigatran, 131 (130.5-135.5) minutes, respectively. Times in patients on warfarin were, 137 (136.5-143.5); in vitro low-dose apixaban, 141 (138.5-142); and patients on apixaban, 140 (138-142.5) minutes, respectively. No thrombus formed in the in vitro high-dose apixaban group. There were no significant differences between the individual groups. When all apixaban groups were compared with nonapixaban groups, the time to thrombosis formation was significantly longer, 143 (137-150) versus 133.5 (128.5-140) minutes, P=0.02. There were similar changes in lactate dehydrogenase levels and other secondary end points. CONCLUSIONS: In an in vitro study of anticoagulation using human blood in a mock loop with a HeartWare HVAD, we demonstrated similar thrombosis times for apixaban and warfarin. Time to clotting was longer in the combined apixaban groups compared with combined other groups, but thrombosis times between individual groups were not significantly different.

Association analysis of transcripts from the bipolar susceptibility locus on chromosome 4q35, exclusion of a pathogenic role for eight positional candidate genes.

Bipolar affective disorder is a major psychiatric illness with a population prevalence of up to 1.6%. The disorder is genetically complex. To date, no specific gene or DNA sequence variation that predisposes to the disorder has been described, however several susceptibility loci have been proposed through genetic linkage analysis. We previously identified one such susceptibility locus on chromosome 4q35, and refined the interval harboring this susceptibility gene to a size that is amenable to positional cloning. Several independent studies have now been described that support the presence of a susceptibility gene at this locus. In order to identify candidate genes for testing association with bipolar disorder, we previously established a comprehensive transcript map that encompasses the chromosome 4q35 susceptibility locus implicated in our linkage analysis. In this study, we have selected full-length genes from the transcript map and determined the genomic structure of each gene. We identified informative, intragenic single nucleotide polymorphisms (SNPs) by screening all exons and flanking intron sequences in affected individuals from seven bipolar pedigrees that we previously reported as showing evidence for linkage to chromosome 4q35. Analysis of these SNPs was then extended to our unrelated bipolar case-control cohort to test for association with the disorder. Our data suggests that all genes analyzed can be excluded from direct involvement in the disorder. We have therefore, excluded approximately half the genes within the chromosome 4q35 candidate interval from playing a direct pathogenic role in bipolar disorder.