Machine Learning Models Identify Inhibitors of New Delhi Metallo-ß-lactamase.

The worldwide spread of the metallo-ß-lactamases (MBL), especially New Delhi metallo-ß-lactamase-1 (NDM-1), is threatening the efficacy of ß-lactams, which are the most potent and prescribed class of antibiotics in the clinic. Currently, FDA-approved MBL inhibitors are lacking in the clinic even though many strategies have been used in inhibitor development, including quantitative high-throughput screening (qHTS), fragment-based drug discovery (FBDD), and molecular docking. Herein, a machine learning-based prediction tool is described, which was generated using results from HTS of a large chemical library and previously published inhibition data. The prediction tool was then used for virtual screening of the NIH Genesis library, which was subsequently screened using qHTS. A novel MBL inhibitor was identified and shown to lower minimum inhibitory concentrations (MICs) of Meropenem for a panel of E. coli and K. pneumoniae clinical isolates expressing NDM-1. The mechanism of inhibition of this novel scaffold was probed utilizing equilibrium dialyses with metal analyses, native state electrospray ionization mass spectrometry, UV-vis spectrophotometry, and molecular docking. The uncovered inhibitor, compound 72922413, was shown to be 9-hydroxy-3-[(5-hydroxy-1-oxa-9-azaspiro[5.5]undec-9-yl)carbonyl]-4H-pyrido[1,2-a]pyrimidin-4-one.

Implementation of supplemental physiotherapy following hip fracture surgery: a protocol for the process evaluation of a randomised controlled trial.

BACKGROUND: Patient outcomes following low-trauma hip fracture are suboptimal resulting in increased healthcare costs and poor functional outcomes at 1 year. Providing early and intensive in-hospital physiotherapy could help improve patient outcomes and reduce costs following hip fracture surgery. The HIP fracture Supplemental Therapy to Enhance Recovery (HIPSTER) trial will compare usual care physiotherapy to intensive in-hospital physiotherapy for patients following hip fracture surgery. The complex environments in which the intervention is implemented present unique contextual challenges that may impact intervention effectiveness. This study aims to complete a process evaluation to identify barriers and facilitators to implementation and explore the patient, carer and clinician experience of intensive therapy following hip fracture surgery. METHODS AND ANALYSIS: The process evaluation is embedded within a two-arm randomised, controlled, assessor-blinded trial recruiting 620 participants from eight Australian hospitals who have had surgery for a hip fracture sustained via a low-trauma injury. A theory-based mixed method process evaluation will be completed in tandem with the HIPSTER trial. Patient and carer semi-structured interviews will be completed at 6 weeks following hip fracture surgery. The clinician experience will be explored through online surveys completed pre- and post-implementation of intensive therapy and mapped to domains of the Theoretical Domains Framework (TDF). Translation and behaviour change success will be assessed using the Reach Effectiveness-Adoption Implementation Maintenance (RE-AIM) framework and a combination of qualitative and quantitative data collection methods. These data will assist with the development of an Implementation Toolkit aiding future translation into practice. DISCUSSION: The embedded process evaluation will help understand the interplay between the implementation context and the intensive therapy intervention following surgery for low-trauma hip fracture. Understanding these mechanisms, if effective, will assist with transferability into other contexts and wider translation into practice. TRIAL REGISTRATION: ACTRN 12622001442796.

Gender differences in female and male Australian football concussion injury: A prospective observational study of emergency department presentations.

OBJECTIVE: To examine gender differences in Australian football (AF)-related concussion presentations to EDs in regional Australia. METHODS: A prospective observational study of patients presenting to 1 of the 10 EDs in Western Victoria, Australia, with an AF-related concussion was conducted. Patients were part of a larger study investigating AF injuries over a complete AF season, including pre-season training and practice matches. Information regarding concussion injuries was extracted from patient medical records, including clinical features, concurrent injuries, mechanism and context of injury. Female and male data were compared with chi-squared and Fisher's exact tests. P < 0.05 was considered significant. RESULTS: From the original cohort of 1635 patients with AF-related injuries (242 female and 1393 male), 231 (14.1%) patients were diagnosed with concussion. Thirty-eight (15.7%) females had concussions versus 193 (13.9%) males (P > 0.05). Females over the age of 16 were more likely to be concussed than males in the same age range (females n = 26, 68.4% vs males n = 94, 48.7%; P = 0.026). Neurosurgically significant head injury was rare (one case). Similar rates of concurrent injury were found between females 15 (39.5%) and males 64 (33.2%), with neck injury the single most common in 24 (10.3%) concussions. Sixty-nine patients (29%) were admitted for observation or to await the results of scans. The majority of concussions occurred in match play (87.9%). Females were more likely injured in contested ball situations (63.2% vs 37.3%; P < 0.05). CONCLUSION: Concussion rates for community-level AF presentations to regional EDs were similar between genders. Serious head injury was rare, although hospital admission for observation was common. Concurrent injuries were common, with associated neck injury most often identified. Match play accounted for the majority of head injuries.

Comparable low revision rates of stemmed and stemless total anatomic shoulder arthroplasties after exclusion of metal backed glenoid components: a collaboration between the Australian and Danish national shoulder arthroplasty registries.

BACKGROUND: The stemmed anatomical total shoulder arthroplasty is the gold standard in the treatment of glenohumeral osteoarthritis. However, the use of stemless total shoulder arthroplasties has increased in recent years. The number of revision procedures are relatively low and therefore it has been recommended that national joint replacement registries should collaborate when comparing revision rates. Therefore, we aimed to compare the revision rates of stemmed and stemless TSA used for the diagnosis of glenohumeral osteoarthritis using data from both the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) and the Danish Shoulder Arthroplasty Registry (DSR). METHODS: We included all patients who were registered in the AOANJRR and the DSR from January 1 2012 to December 2021 with an anatomical total shoulder arthroplasty used for osteoarthritis. Revision for any reason was used as the primary outcome. We used the Kaplan-Meier method to illustrate the cumulative revision rates and a multivariate cox regression model to calculate the hazard ratios. All analyses were performed separately for data from AOANJRR and DSR, and the results were then reported using a qualitative approach. RESULTS: 13066 arthroplasties from AOANJRR and 2882 arthroplasties from DSR were included. The hazard ratio for revision of stemmed TSA with stemless TSA as reference, adjusted for age and gender, was 1.67 (95% CI 1.34-2.09, p<0.001) in AOANJRR and 0.57 (95% CI 0.36-0.89, p=0.014) in DSR. When including glenoid type and fixation, surface bearing (only in AOANJRR) and hospital volume in the cox regression model the hazard ratio for revision of stemmed TSA compared to stemless TSA was 1.22 (95% CI 0.85-1.75, p=0.286) in AOANJRR and 1.50 (95% CI 0.91-2.45, p=0.109) in DSR. The adjusted hazard ratio for revision of total shoulder arthroplasties with metal backed glenoid components compared to all-polyethylene glenoid components was 2.54 (95% CI 1.70-3.79, p < 0.001) in AOANJRR and 4.1 (95% CI 1.92-8.58, p<0.001) in DSR. CONCLUSION: Based on data from two national shoulder arthroplasty registries, we found no significant difference in risk of revision between stemmed and stemless total shoulder arthroplasties after adjusting for the type of glenoid component. We advocate that metal-backed glenoid components should be used with caution and not on a routine basis.

Visualizing mitochondrial heme flow through GAPDH in living cells and its regulation by NO.

Iron protoporphyrin IX (heme) is a redox-active cofactor that is bound in mammalian cells by GAPDH and allocated by a process influenced by physiologic levels of NO. This impacts the activity of many heme proteins including indoleamine dioxygenase-1 (IDO1), a redox enzyme involved in immune response and tumor growth. To gain further understanding we created a tetra-Cys human GAPDH reporter construct (TC-hGAPDH) which after labeling could indicate its heme binding by fluorescence quenching. When purified or expressed in a human cell line, TC-hGAPDH had properties like native GAPDH and heme binding quenched its fluorescence by 45-65%, allowing it to report on GAPDH binding of mitochondrially-generated heme in live cells in real time. In cells with active mitochondrial heme synthesis, low-level NO exposure increased heme allocation to IDO1 while keeping the TC-hGAPDH heme level constant due to replenishment by mitochondria. When mitochondrial heme synthesis was blocked, low NO caused a near complete transfer of the existing heme in TC-hGAPDH to IDO1 in a process that required IDO1 be able to bind the heme and have an active hsp90 present. Higher NO exposure had the opposite effect and caused IDO1 heme to transfer back to TC-hGAPDH. This demonstrated: (i) flow of mitochondrial heme through GAPDH is tightly coupled to target delivery, (ii) NO up- or down-regulates IDO1 activity by promoting a conserved heme exchange with GAPDH that goes in either direction according to the NO exposure level. The ability to drive a concentration-dependent, reversible protein heme exchange is unprecedented and reveals a new role for NO in biology.

Emergency presentations for farm-related injuries in older adults residing in south-western Victoria, Australia.

INTRODUCTION: Farm workers are at high risk for injuries, and epidemiological data are needed to plan resource allocation. OBJECTIVE: This study identified regions with high farm-related injury rates in the Barwon South West region of Victoria, Australia, for residents aged ≥50 yr. DESIGN: Retrospective synthesis using electronic medical records of emergency presentations occurring during 2017-2019 inclusive for Local Government Areas (LGA) in the study region. For each LGA, age-standardised incidence rates (per 1000 population/year) were calculated. FINDINGS: For men and women combined, there were 31 218 emergency presentations for any injury, and 1150 (3.68%) of these were farm-related. The overall age-standardised rate for farm-related injury presentations was 2.6 (95% CI 2.4-2.7); men had a higher rate than women (4.1, 95% CI 3.9-4.4 versus 1.2, 95% CI 1.0-1.3, respectively). For individual LGAs, the highest rates of farm-related emergency presentations occurred in Moyne and Southern Grampians, both rural LGAs. Approximately two-thirds of farm-related injuries occurred during work activities (65.0%), and most individuals arrived at the hospital by transport classified as "other" (including private car, 83.3%). There were also several common injury causes identified: "other animal related injury" (20.2%), "cutting, piercing object" (19.5%), "fall ⟨1 m" (13.1%), and "struck by or collision with object" (12.5%). Few injuries were caused by machinery (1.7%) and these occurred mainly in the LGA of Moyne (65%). DISCUSSION AND CONCLUSION: This study provides data to inform future research and resource allocation for the prevention of farm-related injuries.

Phage-layer interferometry: a companion diagnostic for phage therapy and a bacterial testing platform.

The continuing and rapid emergence of antibiotic resistance (AMR) calls for innovations in antimicrobial therapies. A promising, 're-emerging' approach is the application of bacteriophage viruses to selectively infect and kill pathogenic bacteria, referred to as phage therapy. In practice, phage therapy is personalized and requires companion diagnostics to identify efficacious phages, which are then formulated into a therapeutic cocktail. The predominant means for phage screening involves optical-based assays, but these methods cannot be carried out in complex media, such as colored solutions, inhomogeneous mixtures, or high-viscosity samples, which are often conditions encountered in vivo. Moreover, these assays cannot distinguish phage binding and lysis parameters, which are important for standardizing phage cocktail formulation. To address these challenges, we developed Phage-layer Interferometry (PLI) as a companion diagnostic. Herein, PLI is assessed as a quantitative phage screening method and prototyped as a bacterial detection platform. Importantly, PLI is amenable to automation and is functional in complex, opaque media, such as baby formula. Due to these newfound capabilities, we foresee immediate and broad impact of PLI for combating AMR and protecting against foodborne illnesses.

Post-Activation Performance Enhancement of Punch Force and Neuromuscular Performance in Amateur Boxing: Toward a More Individualized and "Real-World" Approach.

ABSTRACT: Finlay, MJ, Greig, M, Bridge, CA, and Page, RM. Post-activation performance enhancement of punch force and neuromuscular performance in amateur boxing: Toward a more individualized and "real-world" approach. J Strength Cond Res 38(6): 1063-1071, 2024-Previous research on post-activation performance enhancement has been applied in several sporting settings, although this is lacking in a boxing setting. This study explored the effectiveness of 2 upper-body conditioning activities in improving punch-specific performance during an amateur boxing-simulated bout. On 3 separate occasions, 10 male senior elite amateur boxers performed the following conditioning activities before a boxing-specific simulation protocol: isometric (ISO) punch, elastic resistance (ER) punch, and a control trial. Boxers performed maximal punches against a vertically mounted force plate, and countermovement jumps (CMJ) at baseline, before round 1, after each round, and 4 minutes after the simulation. Both conditioning activities, but not the control trial, produced small worthwhile increases (effect size ≥ 0.20; equal to or greater than the smallest worthwhile change) in punch force, although worthwhile increases in rate of force development were limited to the cross during the ISO trial. No group-based improvements in CMJ performance were observed. Individual analysis revealed that 6 boxers improved punch-specific performance to the greatest extent in the ISO trial; in contrast, only 1 boxer did so in the ER trial. Three boxers exhibited similar performance increases across trials. In conclusion, both conditioning activities may be applied to an amateur boxer's warm-up to acutely enhance punch-specific performance. The ISO conditioning activity seems most effective; however, the interindividual variability suggests a need for protocols to be individualized to each athlete. The conditioning activities in the present study may be applied to sparring, competitive bouts, or to other combat sports.

HIP fracture Supplemental Therapy to Enhance Recovery (HIPSTER): a protocol for a randomised controlled trial.

INTRODUCTION: Hip fractures result in substantial health impacts for patients and costs to health systems. Many patients require prolonged hospital stays and up to 60% do not regain their prefracture level of mobility within 1 year. Physical rehabilitation plays a key role in regaining physical function and independence; however, there are no recommendations regarding the optimal intensity. This study aims to compare the clinical efficacy and cost-effectiveness of early intensive in-hospital physiotherapy compared with usual care in patients who have had surgery following a hip fracture. METHODS AND ANALYSIS: This two-arm randomised, controlled, assessor-blinded trial will recruit 620 participants who have had surgery following a hip fracture from eight hospitals. Participants will be randomised 1:1 to receive usual care (physiotherapy according to usual practice at the site) or intensive physiotherapy in the hospital over the first 7 days following surgery (two additional sessions per day, one delivered by a physiotherapist and the other by an allied health assistant). The primary outcome is the total hospital length of stay, measured from the date of hospital admission to the date of hospital discharge, including both acute and subacute hospital days. Secondary outcomes are functional mobility, health-related quality of life, concerns about falling, discharge destination, proportion of patients remaining in hospital at 30 days, return to preadmission mobility and residence at 120 days and adverse events. Twelve months of follow-up will capture data on healthcare utilisation. A cost-effectiveness evaluation will be undertaken, and a process evaluation will document barriers and facilitators to implementation. ETHICS AND DISSEMINATION: The Alfred Hospital Ethics Committee has approved this protocol. The trial findings will be published in peer-reviewed journals, submitted for presentation at conferences and disseminated to patients and carers. TRIAL REGISTRATION NUMBER: ACTRN12622001442796.

Measurement Properties of the Oxford Shoulder Score and Minimal Clinically Important Changes After Primary Total Shoulder Replacement Surgery.

OBJECTIVE: We evaluated the measurement properties of the Oxford Shoulder Score (OSS) and estimated the minimal clinically important change (MCIC) in patients undergoing primary total shoulder replacement in Australia. METHODS: Deidentified data from the Australian Orthopaedic Association National Joint Replacement Registry were used for this analysis. Pre- and 6-month postoperative OSS scores were used, with the 5-level EuroQoL quality of life instrument and shoulder pain scores used as comparators. Floor and ceiling effects, internal consistency reliability, construct validity, and responsiveness to change were evaluated using standard psychometric methods. Mean change and predictive modeling approaches (with and without adjustment for the proportion of improved patients) were used to calculate MCIC thresholds, with patient-perceived improvement after surgery as the anchor. RESULTS: Preoperative OSS data were available for 1,117 patients (59% female; 90% aged ≥60 years) undergoing primary total shoulder replacement. No floor or ceiling effects were observed pre- or postoperatively. The OSS showed high internal consistency reliability (Cronbach alpha >0.89), good construct validity, and high responsiveness to change (effect size 1.88). The MCIC derived from the mean change method was 6.50 points (95% confidence interval [95% CI] 4.41-8.61). The predictive modeling approach produced an MCIC estimate of 8.42 points (95% CI 5.68-12.23) after adjustment. CONCLUSION: The OSS has good measurement properties to capture pain and function outcomes after shoulder replacement procedures and is highly responsive to change. Based on robust methods, an increase in OSS scores of at least eight points can be considered as meaningful improvement after surgery from the patient's perspective.

Visualizing Mitochondrial Heme Flow through GAPDH to Targets in Living Cells and its Regulation by NO.

Iron protoporphyrin IX (heme) is an essential cofactor that is chaperoned in mammalian cells by GAPDH in a process regulated by NO. To gain further understanding we generated a tetra-Cys human GAPDH reporter construct (TC-hGAPDH) which after being expressed and labeled with fluorescent FlAsH reagent could indicate heme binding by fluorescence quenching. When purified or expressed in HEK293T mammalian cells, FlAsH-labeled TC-hGAPDH displayed physical, catalytic, and heme binding properties like native GAPDH and its heme binding (2 mol per tetramer) quenched its fluorescence by 45-65%. In live HEK293T cells we could visualize TC-hGAPDH binding mitochondrially-generated heme and releasing it to the hemeprotein target IDO1 by monitoring cell fluorescence in real time. In cells with active mitochondrial heme synthesis, a low-level NO exposure increased heme allocation into IDO1 while keeping steady the level of heme-bound TC-hGAPDH. When mitochondrial heme synthesis was blocked at the time of NO exposure, low NO caused cells to reallocate existing heme from TC-hGAPDH to IDO1 by a mechanism requiring IDO1 be present and able to bind heme. Higher NO exposure had an opposite effect and caused cells to reallocate existing heme from IDO1 to TC-hGAPDH. Thus, with TC-hGAPDH we could follow mitochondrial heme as it travelled onto and through GAPDH to a downstream target (IDO1) in living cells, and to learn that NO acted at or downstream from the GAPDH heme complex to promote a heme reallocation in either direction depending on the level of NO exposure.

A comparison of revision rates for stemmed and stemless primary anatomic shoulder arthroplasty with all-polyethylene glenoid components: analysis from the Australian Orthopaedic Association National Joint Replacement Registry.

BACKGROUND: We compared the rate of all-cause revision of 2 classes of primary anatomic shoulder arthroplasty, stemmed (stTSA) and stemless (slTSA), undertaken with cemented all-polyethylene glenoid components. METHODS: A large national arthroplasty registry identified 2 cohort groups for comparison, stTSA and l undertaken for all diagnoses between January 1, 2011, and December 31, 2021. A subanalysis from January 1, 2017, allowed capturing of additional patient demographics including American Society of Anesthesiologists score, body mass index, and glenoid morphology. The cumulative percent revision (CPR) was determined using Kaplan-Meier estimates of survivorship and hazard ratios (HR) from Cox proportional hazard models adjusted for age and gender. RESULTS: Of the 7995 stTSA procedures, the CPR at 9 years was 5.6% (95% confidence interval [CI]: 5.0, 6.4), and for 3156 slTSA procedures, the CPR was 4.4% (95% CI: 3.6, 5.5). There was no significant difference in the rate of revision between the study groups (HR = 0.76 [95% CI: 0.51, 1.14], P = .189, adjusted for age, gender, humeral head size, humeral fixation, bearing surface, glenoid design, and mean surgeon volume [MSV]). There was an increased rate of revision for stTSA and slTSA undertaken with humeral head sizes <44 mm (stTSA <44 mm vs. 44-50 mm, HR = 1.56 [CI: 1.18, 2.08], P = .001; slTSA <44 mm vs. 44-50 mm, HR = 2.08 [CI: 1.32, 3.33], P = .001). MSV as a continuous predictor was not a revision risk to stTSA vs. slTSA, but categorically, a low MSV (<10 stTSA + slTSA cases per annum) was associated with a higher revision rate for stTSA (10-20 cases/yr vs. <10 cases/yr, HR = 0.72 [CI: 0.55, 0.95], P = .019) but was not in slTSA. Revision rates were increased for stTSA with non-crosslinked polyethylene (XLPE) glenoids vs. XPLE after 2 years (HR = 2.20 [CI: 1.57, 3.08], P < .001) but did not significantly differ for slTSA. Metal/XPLE (humeral/glenoid) bearing surface of stTSA rate of revision was not different from each combination of slTSA bearing surface. Instability/dislocation was a revision risk for slTSA vs. stTSA (HR = 1.93 [CI: 1.28, 2.91], P = .001), but from 2017, neither of American Society of Anesthesiologists score, body mass index, and glenoid morphology changed the rate of revision. CONCLUSIONS: Revision rates of stTSA and slTSA did not significantly differ and were associated with humeral head size but not patient characteristics. Surgeon inexperience of anatomic shoulder arthroplasty and non-XLPE glenoids were risk factors for stTSA revision but not slTSA. The metal/XLPE stTSA rate of revision was not found to differ significantly from slTSA regardless of polyethylene or humeral head bearing type. Revision for instability/dislocation was more common for slTSA.

Distal humeral hemiarthroplasty compared to total elbow replacement for distal humeral fractures: a registry analysis of 906 procedures.

BACKGROUND: Total elbow replacement (TER) is an accepted treatment for complex intra-articular distal humerus fractures in elderly patients. Distal humeral hemiarthroplasty (HA) is also a potential surgical option for unreconstructable fractures and avoids the concerns regarding mechanical wear and functional restrictions associated with TER. In the current literature, there are limited data available to compare the revision rates of HA and TER for the treatment of fracture. We used data from a large national arthroplasty registry to compare the outcome of HA and TER undertaken for fracture/dislocation and to assess the impact of demographics and implant choice on revision rates. METHODS: Data obtained from the Australian Orthopaedic Association National Joint Replacement Registry from May 2, 2005, to December 31, 2021, included all procedures for primary elbow replacement with primary diagnosis of fracture or dislocation. The analyses were performed using Kaplan-Meier estimates of survivorship and hazard ratios (HRs) from Cox proportional hazards models. RESULTS: There were 293 primary HA and 631 primary TER procedures included. The cumulative percentage revision (CPR) rate at 9 years was 9.7% for HA (95% confidence interval [CI] 6.0, 15.7), and 11.9% (95% CI 8.5, 16.6) for TER. When adjusted for age and gender, there was a significantly higher risk of revision after 3 months for TER compared to HA (HR 2.47, 95% CI 1.22, 5.03, P = .012). There was no difference in the rate of revision for patients aged <55 years or ≥75 years when HA and TER procedures were compared. In primary TER procedures, loosening was the most common cause of revision (3.6% of primary TER procedures), and the most common type of revision in primary TER involved revision of the humeral component only (2.6% of TER procedures). TER has a higher rate of first revision for loosening compared to HA (HR 4.21, 95% CI 1.29, 13.73; P = .017). In HA procedures, instability (1.7%) was the most common cause for revision. The addition of an ulna component was the most common type of revision (2.4% of all HA procedures). CONCLUSION: For the treatment of distal humerus fractures, HA had a lower revision rate than TER after 3 months when adjusted for age and gender. Age <55 or ≥75 years was not a risk factor for revision when HA was compared to TER. Loosening leading to revision is more prevalent in TER and increases with time. In HA, the most common type of revision involved addition of an ulna component with preservation of the humeral component.

The moment arms and lines of action of subscapularis after the Latarjet procedure.

The Latarjet procedure is an established surgical treatment for recurrent glenohumeral joint instability with glenoid bone loss. Intraoperatively, the conjoint tendon and its attachement on the coracoid bone graft is routed through a split in subscapularis where the graft is fixed to and augments the anteroinferior glenoid. The objective of this in vitro study was to quantify the influence of glenohumeral joint position and conjoint tendon force on the lines of action and moment arms of subscapularis muscle sub-regions after Latarjet surgery. Eight fresh-frozen, entire upper extremities were mounted onto a testing apparatus, and a cable-pulley system was used to apply physiological muscle loading to the major shoulder muscles. The lines of action and moment arms of four subregions of subscapularis (superior, mid-superior, mid-inferior, and inferior) were quantified radiographically with the conjoint tendon unloaded and loaded while the shoulder was in (i) 0° abduction (ii) 90° abduction (iii) 90° abduction and full external rotation (ABER), and (iv) the apprehension position, defined as ABER with 30° horizontal extension. Conjoint tendon loading after Latarjet surgery significantly increased the inferior inclination of the lines of action of the mid-inferior and inferior subregions of subscapularis in the scapular plane in ABER and apprehension positions (p < 0.001), as well as decreased the horizontal flexion moment arm of the inferior subscapularis (p = 0.040). Increased subscapularis inferior inclination may ultimately increase inferior joint shear potential, while smaller horizontal flexion leverage may reduce joint flexion capacity. The findings have implications for Latarjet surgical planning and postoperative rehabilitation prescription.

Long-term clinical and radiological outcomes following arthroscopic microfracture of the glenohumeral joint for chondral defects.

Background: The primary aim of this study was to evaluate mid- and long-term outcomes following microfracture in patients with glenohumeral chondral lesions. Methods: This prospective cohort study assessed patients with shoulder pain who were treated with arthroscopic microfracture for full-thickness chondral lesions of the glenohumeral joint. Outcomes included the Simple Shoulder Test at baseline, mid-term (approximately 1 year) and long-term (approximately 10 years), and the Oxford Shoulder Score, shoulder pain (0-10 numerical scale) and radiological assessment using a modified Samilson & Prieto score at long-term follow-up. Data were analyzed with paired t-tests and Wilcoxon's signed rank tests, which were considered significant if P < .05. Results: Twenty-five patients with a mean age of 52.7 ± 12.1 were enrolled. The mean Simple Shoulder Test score improved from baseline to 1 year (6.7 ± 2.5 to 11.0 ± 1.4, P < .001), which was maintained at long-term follow-up (10.3 ± 2.1, P < .001). Additionally, at long-term follow-up, Oxford Shoulder Score and Verbal Pain Score scores were 43 ± 4.8 and 1.1 ± 1.5, respectively while median modified Samilson & Prieto scores increased from 1 preoperatively to 2 at 10 years (P < .001). Conclusion: Patients undergoing microfracture for full-thickness chondral lesions of the glenohumeral joint reported substantial improvements in shoulder pain and function at 1 and 10 years, despite progressive radiological degeneration.

Primary inlay reverse shoulder arthroplasty has a higher rate of revision than onlay reverse shoulder arthroplasty: Analysis from the Australian Orthopaedic Association National Joint Replacement Registry.

Background: Two classes of primary reverse total shoulder arthroplasty (rTSA), inlay (in-rTSA), and onlay (on-rTSA) were compared to determine differences in rates of revision. Methods: Between 1 January 2012 and 31 December 2020, all primary in-rTSA or on-rTSA procedures were compared from a large national arthroplasty registry by cumulative percentage revision (CPR). Kaplan-Meier estimates of survivorship and hazard ratios from Cox proportional hazard models adjusted for age, gender, glenosphere size, and humeral fixation determined any associations to the risk of revision. Results: Of the 14,807 in-rTSA and 6590 on-rTSA procedures, the CPR at seven years was 4.9%. There was an increased risk of revision for in-rTSA vs on-rTSA (p = 0.039) when adjusted for age, gender, glenosphere size, and humeral fixation. Glenosphere size <38 mm adjusted for age and gender (p = 0.016) increased the revision risk. Revision for instability/dislocation occurred more often for in-rTSA vs on-rTSA (p < 0.001) in the first three months. Males had a higher rate of revision than females for in-rTSA (3months+, p = 0.001) and for on-rTSA (p < 0.001). Discussion: Care should be taken when considering in-rTSA particularly in males, and if preoperative planning suggests a small (<38 mm) glenosphere. Level of evidence: Level III, therapeutic study. Original article.

The directed evolution of NDM-1.

ß-Lactam antibiotics are among the most frequently prescribed therapeutic agents. A common mechanism of resistance toward ß-lactam antibiotics is the production of ß-lactamases. These enzymes are capable of hydrolyzing the ß-lactam bond, rendering the drug inactive. Among the four described classes, the metallo- ß-lactamases (MBLs, class B) employ one or two zinc ions in the active site for catalysis. One of the three most clinically relevant MBLs is New Delhi Metallo- ß-Lactamase (NDM-1). The current study sought to investigate the in vitro protein evolution of NDM-1 ß-lactamase using error-prone polymerase chain reaction. Evaluation revealed that variants were not found to confer higher levels of resistance toward meropenem based on amino acid substitutions. Thus, we postulate that increases in transcription or changes in zinc transport may be clinically more relevant to meropenem resistance than amino acid substitutions.

Ubiquitination detection techniques.

Ubiquitination is an intricately regulated post-translational modification that involves the covalent attachment of ubiquitin to a substrate protein. The complex dynamic nature of the ubiquitination process regulates diverse cellular functions including targeting proteins for degradation, cell cycle, deoxyribonucleic acid (DNA) damage repair, and numerous cell signaling pathways. Ubiquitination also serves as a crucial mechanism in protein quality control. Dysregulation in ubiquitination could result in lethal disease conditions such as cancers and neurodegenerative diseases. Therefore, the ubiquitination cascade has become an attractive target for therapeutic interventions. Enormous efforts have been made to detect ubiquitination involving different detection techniques to better grasp the underlying molecular mechanisms of ubiquitination. This review discusses a wide range of techniques stretching from the simplest assays to real-time assays. This includes western blotting/immunoblotting, fluorescence assays, chemiluminescence assays, spectrophotometric assays, and nanopore sensing assays. This review compares these applications, and the inherent advantages and limitations.

Arthroscopic knots: Suture and knot characterisation of modern polyblend suture materials.

Objective: The primary aim of this study was to explore the relationship between the biophysical structure and function of modern suture materials. Particularly the suture's ability to withstand the stressors of surgery and how the material properties affect knot stability. The secondary aim was to investigate the effect that different knots have on the suture material itself. This study builds on previous research assessing suture and knot characteristics but in modern Ultra High Molecular Weight Polyethylene (UHMWPE) materials currently in widespread clinical use in arthroscopic surgery. Methods: Three common UHMWPE sutures and one polyester suture were tested in both a dry and wet state using the Geelong, Nicky's, Surgeon's and Tautline knots. Tensile strength of knots was tested vertically at a 60 mm/min strain rate and 45 mm gauge length. Sutures were tied through a cannula around two 8 mm diameter circular bollards. Testing was conducted in a controlled environment temperature and humidity environment (20 ± 2 °C, 65 ± 2%). Results: No one knot type was optimal over all suture types. Mean tensile strength in both a dry and wet state and a low coefficient of variation (CV) in tensile strength in a wet state were considered as an indication of suitability. With Ethibond sutures this was the Geelong knot (CV:4.2%). With Orthocord sutures both the Geelong and Tautline knots (CV:4.2% and CV:11.9% respectively). With FiberWire sutures the Nickys and Tautline knots (CV:22.6% and CV:22.5% respectively). With ForceFiber sutures all four knots exhibited similar wet tensile strength with high variability showing that all should perform in a similar way invivo. Conclusions: This study demonstrates a statistically significant three-way interaction between polyblend suture materials, the knot and the environment. This has implications for knot security using the tested sutures in different environments, as one knot may not behave the same under all conditions.