Adjusting expected deaths for mortality displacement during the COVID-19 pandemic: a model based counterfactual approach at the level of individuals.

BACKGROUND: Near-real time surveillance of excess mortality has been an essential tool during the COVID-19 pandemic. It remains critical for monitoring mortality as the pandemic wanes, to detect fluctuations in the death rate associated both with the longer-term impact of the pandemic (e.g. infection, containment measures and reduced service provision by the health and other systems) and the responses that followed (e.g. curtailment of containment measures, vaccination and the response of health and other systems to backlogs). Following the relaxing of social distancing regimes and reduction in the availability of testing, across many countries, it becomes critical to measure the impact of COVID-19 infection. However, prolonged periods of mortality in excess of the expected across entire populations has raised doubts over the validity of using unadjusted historic estimates of mortality to calculate the expected numbers of deaths that form the baseline for computing numbers of excess deaths because many individuals died earlier than they would otherwise have done: i.e. their mortality was displaced earlier in time to occur during the pandemic rather than when historic rates predicted. This is also often termed "harvesting" in the literature. METHODS: We present a novel Cox-regression-based methodology using time-dependent covariates to estimate the profile of the increased risk of death across time in individuals who contracted COVID-19 among a population of hip fracture patients in England (N = 98,365). We use these hazards to simulate a distribution of survival times, in the presence of a COVID-19 positive test, and then calculate survival times based on hazard rates without a positive test and use the difference between the medians of these distributions to estimate the number of days a death has been displaced. This methodology is applied at the individual level, rather than the population level to provide a better understanding of the impact of a positive COVID-19 test on the mortality of groups with different vulnerabilities conferred by sociodemographic and health characteristics. Finally, we apply the mortality displacement estimates to adjust estimates of excess mortality using a "ball and urn" model. RESULTS: Among the exemplar population we present an end-to-end application of our methodology to estimate the extent of mortality displacement. A greater proportion of older, male and frailer individuals were subject to significant displacement while the magnitude of displacement was higher in younger females and in individuals with lower frailty: groups who, in the absence of COVID-19, should have had a substantial life expectancy. CONCLUSION: Our results indicate that calculating the expected number of deaths following the first wave of the pandemic in England based solely on historical trends results in an overestimate, and excess mortality will therefore be underestimated. Our findings, using this exemplar dataset are conditional on having experienced a hip fracture, which is not generalisable to the general population. Fractures that impede mobility in the weeks that follow the accident/surgery considerably shorten life expectancy and are in themselves markers of significant frailty. It is therefore important to apply these novel methods to the general population, among whom we anticipate strong patterns in mortality displacement - both in its length and prevalence - by age, sex, frailty and types of comorbidities. This counterfactual method may also be used to investigate a wider range of disruptive population health events. This has important implications for public health monitoring and the interpretation of public health data in England and globally.

Comparative retrieval analysis of contemporary mobile and fixed unicompartmental knee bearing designs.

There are two different concepts behind Unicompartmental Knee Replacement (UKR). Mobile bearings, as exemplified by the Oxford UKR, and fixed bearings, as exemplified by the Physica ZUK. These are the two most commonly implanted UKRs in the UK. For the first time, a comparison of the tribological features of 19 explanted Oxford and 19 explanted Physica ZUK UKRs was undertaken. Surface damage on the polyethylene (PE) inserts of the Oxford and Physica ZUK cohorts were assessed using an established semi-quantitative scoring method. The femoral components of both cohorts were assessed using a non-contact 3D profilometer to measure roughness values. It was found that the PE inserts of the Oxford cohort (22.54 ± 9.14) had statistically significant greater damage scores than the Physica ZUK cohort (16.50 ± 5.17) (p = 0.04). However, the femoral components of the Oxford cohort showed lower roughness values than the Physica ZUK cohort (p = 0.00). This is the first study that reports a comparative roughness analysis between retrieved Oxford and Physica ZUK UKR designs.

Sagittal flexion arc evaluation for a modern generation single-radius femoral component design.

Single-radius femoral total knee design aims to deliver improved kinematic behaviour when compared to the standard two-radii geometry. This study has evaluated the behaviour, through a functional range of motion in the sagittal plane, of a single-radius femoral component compared to a dual-radius standard knee construct. Particular focus was placed on how the flexion axes of the native and replaced knee approximated to the transepicondylar axis through a loaded navigated knee design. Significant differences in flexion arcs were noted between the native and total knee arthroplasty state. These arcs were not uniform in all knees and did not display single-radius behaviour. There were no significant differences in the location of flexion axes in the native and total knee arthroplasty knee. Both exhibited similar posterior and inferior transverse axes of motion with respect to the anatomical epicondylar axis. This work has cast doubt on the reliability under loaded conditions of the single-radius concept, but the close proximity of the flexion axes of each replaced knee in relation to the functional flexion axis of the native knee may be the true basis of this purported improved kinematic performance.

Tibiofemoral forces for the native and post-arthroplasty knee: relationship to maximal laxity through a functional arc of motion.

PURPOSE: Accurate soft tissue balance must be achieved to improve functional outcome after total knee arthroplasty (TKA). Sensor-integrated tibial trials have been introduced that allow real-time measurement of tibiofemoral kinematics during TKA. This study examined the interplay between tibiofemoral force and laxity, under defined intraoperative conditions, so as to quantify the kinematic behaviour of the CR femoral single-radius knee. METHODS: TKA was undertaken in eight loaded cadaveric specimens. Computer navigation in combination with sensor data defined laxity and tibiofemoral contact force, respectively, during manual laxity testing. Fixed-effect linear modelling allowed quantification of the effect for flexion angle, direction of movement and TKA implantation upon the knee. RESULTS: An inverse relationship between laxity and contact force was demonstrated. With flexion, laxity increased as contact force decreased under manual stress. Change in laxity was significant beyond 30° for coronal plane laxity and beyond 60° for rotatory laxity (p < 0.01). Rotational stress in mid-flexion demonstrated the greatest mismatch in inter-compartmental forces. Contact point position over the tibial sensor demonstrated paradoxical roll-forward with knee flexion. CONCLUSION: Traditional balancing techniques may not reliably equate to uniform laxity or contact forces across the tibiofemoral joint through a range of flexion and argue for the role of per-operative sensor use to aid final balancing of the knee.

Targeting Toll-like receptor 4 prevents cobalt-mediated inflammation.

Cobalt-chrome alloy is a widely used biomaterial in joint replacements, dental implants and spinal rods. Although it is an effective and biocompatible material, adverse reactions to metal debris (ARMD) have arisen in a minority of patients, particularly in those with metal-on-metal bearing hip replacements. There is currently no treatment for ARMD and once progressive, early revision surgery of the implant is necessary. Therapeutic agents to prevent, halt or reverse ARMD would therefore be advantageous. Cobalt ions activate Toll-like receptor 4 (TLR4), an innate immune receptor responsible for inflammatory responses to bacterial lipopolysaccharide (LPS) resulting in the production of pro-inflammatory cytokines and chemokines. We hypothesised that anti-TLR4 neutralising antibodies, reported to inhibit TLR4-mediated inflammation, could prevent the inflammatory response to cobalt ions in an in vitro macrophage cell culture model. This study shows that a monoclonal anti-TLR4 antibody inhibited cobalt-mediated increases in pro-inflammatory IL8, CCL20 and IL1A expression, as well as IL-8 secretion. In contrast, a polyclonal antibody did not prevent the effect of cobalt ions on either IL-8 or IL1A expression, although it did have a small effect on the CCL20 response. Interestingly, both antibodies inhibited cobalt-mediated neutrophil migration although the greater effect was observed with the monoclonal antibody. In summary our data shows that a monoclonal anti-TLR4 antibody can inhibit cobalt-mediated inflammatory responses while a polyclonal antibody only inhibits the effect of specific cytokines. Anti-TLR4 antibodies have therapeutic potential in ARMD although careful antibody design is required to ensure that the LPS response is preserved.

The role of the rotating hinge prosthesis in the salvage arthroplasty setting.

We have studied a consecutive series of 72 salvage knee procedures using a Kinematic rotating hinge prosthesis performed in a single arthroplasty unit between 1983 and 1997. Clinical and radiographic assessment of the survivorship of the Kinematic rotating hinge total knee arthroplasty (Howmedica, Rutherford, NJ) were analyzed. Survival analysis revealed a best-case 10-year implant survival of 90%. Concurrently, this group of patients exhibited a significant and sustained improvement in Knee Society Score and pain relief after implantation of a rotating hinge component. There were 10 deaths due to unrelated causes during the study period. This constrained hinged prosthesis remains a viable option in the face of gross deformity, bone loss, and failed multiple previous surgical procedures.