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Cardinality matching versus propensity score matching for addressing cluster-level residual confounding in implantable medical device and surgical epidemiology: a parametric and plasmode simulation study.
BACKGROUND: Rapid innovation and new regulations lead to an increased need for post-marketing surveillance of implantable devices. However, complex multi-level confounding related not only to patient-level but also to surgeon or hospital covariates hampers observational studies of risks and benefits. We conducted parametric and plasmode simulations to compare the performance of cardinality matching (CM) vs propensity score matching (PSM) to reduce confounding bias in the presence of cluster-level confounding. METHODS: Two Monte Carlo simulation studies were carried out: 1) Parametric simulations (1,000 iterations) with patients nested in clusters (ratio 10:1, 50:1, 100:1, 200:1, 500:1) and sample size n = 10,000 were conducted with patient and cluster level confounders; 2) Plasmode simulations generated from a cohort of 9981 patients admitted for pancreatectomy between 2015 to 2019 from a US hospital database. CM with 0.1 standardised mean different constraint threshold (SMD) for confounders and PSM were used to balance the confounders for within-cluster and cross-cluster matching. Treatment effects were then estimated using logistic regression as the outcome model on the obtained matched sample. RESULTS: CM yielded higher sample retention but more bias than PSM for cross-cluster matching in most scenarios. For instance, with ratio of 100:1, sample retention and relative bias were 97.1% and 26.5% for CM, compared to 82.5% and 12.2% for PSM. The results for plasmode simulation were similar. CONCLUSIONS: CM offered better sample retention but higher bias in most scenarios compared to PSM. More research is needed to guide the use of CM particularly in constraint setting for confounders for medical device and surgical epidemiology.
Epigenetic drug screening identifies enzyme inhibitors A-196 and TMP-269 as novel regulators of sprouting angiogenesis.
Epigenetic therapy has gained interest in treating cardiovascular diseases, but preclinical studies often encounter challenges with cell-type-specific effects or batch-to-batch variation, which have limited identification of novel drug candidates targeting angiogenesis. To address these limitations and improve the reproducibility of epigenetic drug screening, we redesigned a 3D in vitro fibrin bead assay to utilize immortalized human aortic endothelial cells (TeloHAECs) and screened a focused compound library with 105 agents. Compared to the established model using primary human umbilical vein endothelial cells, TeloHAECs needed a higher-density fibrin gel for optimal sprouting, successfully forming sprouts under both normoxic and hypoxic cell culture conditions. We identified two epigenetic enzyme inhibitors as novel regulators of sprouting angiogenesis: A196, a selective SUV4-20H1/H2 inhibitor, demonstrated pro-angiogenic effects through increased H4K20me1 levels and upregulation of cell cycle associated genes, including MCM2 and CDK4. In contrast TMP-269, a selective class IIa HDAC inhibitor, exhibited anti-angiogenic effects by downregulating angiogenesis-related proteins and upregulating pro-inflammatory signaling. These findings highlight the suitability of the modified TeloHAEC fibrin bead assay for drug screening purposes and reveal both pro-angiogenic and anti-angiogenic drug candidates with therapeutic potential.
Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial.
BACKGROUND: Older adults (aged ≥70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19 (AZD1222), in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older. METHODS: In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18-55 years, 56-69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged ≥65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2·2 × 1010 virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18-55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56-69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3·5-6·5 × 1010 virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18-55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA80). Cellular responses were assessed using an ex-vivo IFN-γ enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. FINDINGS: Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18-55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56-69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18-55 years group, 22 (73%) of 30 in the 56-69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18-55 years group, 23 (77%) in the 56-69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18-55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898-33 550], n=39; 56-69 years, 16 170 AU/mL [10 233-40 353], n=26; and ≥70 years 17 561 AU/mL [9705-37 796], n=47; p=0·68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA80 at day 42 in the standard-dose groups: 18-55 years, 193 [IQR 113-238], n=39; 56-69 years, 144 [119-347], n=20; and ≥70 years, 161 [73-323], n=47; p=0·40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18-55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841-2428], n=24; 56-69 years: 797 SFCs [383-1817], n=29; and ≥70 years: 977 SFCs [458-1914], n=48). INTERPRETATION: ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.
Desmopressin for prevention of bleeding for thrombocytopenic, critically ill patients undergoing invasive procedures: A randomised, double-blind, placebo-controlled feasibility trial.
Thrombocytopenic patients have an increased risk of bleeding when undergoing invasive procedures. In a multicentre, phase II, blinded, randomised, controlled feasibility trial, critically ill patients with platelet count 100 × 109/L or less were randomised 1:1 to intravenous desmopressin (0.3 µg/kg) or placebo before an invasive procedure. Forty-three participants (18.8% of those eligible) were recruited, with 41 eligible for analysis. Post-procedure bleeding occurred in one of 22 (4.5%) in the placebo arm and zero of 19 in the desmopressin arm. Despite liberal inclusion criteria, there were significant feasibility challenges recruiting patients in the critical care setting prior to invasive procedures.
The impact of routines on emotional and behavioural difficulties in children and on parental anxiety during COVID-19.
BACKGROUND: The Covid-19 pandemic and related public health measures, including lockdowns and school closures, have impacted on mental health of children. AIMS AND HYPOTHESIS: We hypothesised that there would be an association between maintaining a routine during lockdown and both lower emotional and behavioural difficulties in children and lower parental anxiety. Routine was taken as keeping to the same basic activities such as mealtimes and bedtimes. We also hypothesised that children of 'keyworker' parents would have fewer emotional and behavioural symptoms due to having maintained more normal routines. The key reason was that children of keyworkers still attended school or nursery and parents would have been getting up and coming home at the same times as pre-Covid. Keyworker status was defined as those whose work was essential to Covid-19 response, including work in health and social care and other key sectors. METHODS: We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC) to explore associations between maintaining a routine, and emotional and behavioural difficulties in children, using linear regression models. All eligible ALSPAC-G2 participants were sent the survey and the responders are representative of the eligible G2 population. We included measures of parental anxiety. We separately explored associations with having a keyworker parent. We used the Carey Infant Temperament Questionnaire and the Revised Rutter Parent Scale for Preschool Children to establish levels of emotional and behavioural difficulties. The measures were chosen to match previous waves in multi-generations in ALSPAC where they had been shown to be predictive of later mental health in children. The scales measure emotional and behavioural problems. RESULTS: Two hundred eighty-nine parents completed questionnaires about their 411 children. Keeping a routine was associated with emotional and behavioural difficulty scores 5.0 points lower (95% CI -10.0 to -0.1), p = 0.045 than not keeping a routine. Parents who reported keeping a routine had anxiety scores 4.3 points lower (95% CI -7.5 to -1.1), p = 0.009 than those who did not. Children of keyworkers tended to have lower emotional and behavioural difficulty scores [-3.1 (95%CI -6.26 to 0.08), p = 0.056] than children of non-keyworkers. All models were adjusted for relevant potential confounders. CONCLUSION: Maintaining a routine may be beneficial for both child emotional wellbeing and parental anxiety, although it is also possible that lower parental anxiety levels made maintaining a routine easier. Being the child of a keyworker parent during lockdown may have been protective for child emotional wellbeing.
Childhood trajectories of internalising and externalising problems associated with a polygenic risk score for neuroticism in a UK birth cohort study.
BACKGROUND: Neuroticism represents a personality disposition towards experiencing negative emotions more frequently and intensely. Longitudinal studies suggest that neuroticism increases risk of several psychological problems. Improved understanding of how this trait manifests in early life could help inform preventative strategies in those liable to neuroticism. METHODS: This study explored how a polygenic risk score for neuroticism (NEU PRS) is expressed from infancy to late childhood across various psychological outcomes using multivariable linear and ordinal regression models. In addition, we employed a three-level mixed-effect model to characterise child internalising and externalising trajectories and estimate how a child PRS associated with both their overall levels and rates of change in 5279 children aged 3-11 in the Avon Longitudinal Study of Parents and Children cohort. RESULTS: We found evidence that the NEU PRS was associated with a more emotionally sensitive temperament in early infancy in addition to higher emotional and behavioural problems and a higher risk of meeting diagnostic criteria for a variety of clinical disorders, particularly anxiety disorders, in childhood. The NEU PRS was associated with overall levels of internalising and externalising trajectories, with a larger magnitude of association on the internalising trajectory. The PRS was also associated with slower rates of reduction of internalising problems across childhood. CONCLUSIONS: Our findings using a large, well-characterised birth cohort study suggest that phenotypic manifestations of a PRS for adult neuroticism can be detected as early as in infancy and that this PRS associates with several mental health problems and differences in emotional trajectories across childhood.
Higher hospital volume reduces early failure rates in single-stage revision TKR for infection: An analysis of the United Kingdom National Joint Registry and National Administrative Databases.
PURPOSE: Revision knee replacement (RevKR) for infection is rare but increasing. It is hypothesised that higher hospital volume reduces adverse outcomes. The aim was to estimate the association of surgical unit volume with outcomes following first, single-stage RevKR for infection. METHODS: This population-based cohort study merged data from the United Kingdom National Joint Registry, Hospital Episode Statistics, National Patient Reported Outcome Measures and the Civil Registrations of Death. Patients undergoing procedures between 1 January 2009 and 30 June 2019 were included. Early outcomes were chosen to reflect the quality of the surgical provision and included re-revision at 2 years, mortality, serious medical complications, length of stay and patient-reported outcome measures (PROMs). Adjusted fixed effect multivariable regression models were used to examine the association between surgical unit mean annual caseload and the risk of adverse outcomes. RESULTS: A total of 1477 patients underwent first-time single-stage RevKRs for infection across 267 surgical units and 716 surgeons. Following adjustment for age, gender, American Society of Anaesthesiologists grade, surgeon volume, year of surgery and operation funder and modelling surgical unit volume with restricted cubic spline, a greater mean annual volume was associated with a lower risk of re-revision at 2 years. The odds of re-revision in hospitals performing fewer than or equal to 12 cases per year was 2.53 (95% confidence interval = 1.50-4.31) times more likely than hospitals performing three to four cases per month. Annual variation in surgical unit volume was not associated with mortality and serious medical complications within 90 days. Only 99 out of 1477 (7%) of patients had linked PROMs which precluded subsequent analysis. CONCLUSION: Overall, higher volume surgical units had lower rates of early re-revision following the first RevKR for infection. We were unable to provide recommended specific volume thresholds for units; however, the probability of re-revision appears to be lowest in the highest volume units. LEVEL OF EVIDENCE: Level III, retrospective cohort study of prospectively collected data.
Preventing pressure sores after hip fracture
Hip fractures commonly occur in older patients, with high levels of frailty and comorbidity. Many of these patients have limited mobility before their fracture, and even after surgery, their mobility may remain limited. It is therefore not surprising that they are at a high risk of developing pressure sores, particularly on their heels, and a variety of devices and interventions have been proposed to reduce this risk. Foam or air mattresses, designed to reduce contact pressure on the patient’s whole body, are now routinely used in many healthcare systems. However, there is wide variation in their design. We developed the WHiTE 14;PRESSURE 3 trial to address the lack of evidence in this area. This is a three-arm multicentre randomized trial including health economic evaluation and recruiting patients from NHS hospitals in the UK. The trial compares standard strategies for the prevention of pressure sores with standard care plus a constant low-pressure device and with standard care plus a heel off-loading device. This annotation describes the development of this trial.Cite this article: Bone Joint J 2025;107-B(2):135–138.
Haemodynamic measurements during hip hemiarthroplasty surgery for hip fracture.
AIMS: There is compelling evidence for the use of cemented hip hemiarthroplasty for displaced intracapsular hip fractures; however, the risks of cement are well reported and in rare cases may be associated with haemodynamic collapse. It is therefore important to improve our understanding of haemodynamic instability, intraoperative monitoring, and strategies to reduce the risk to patients. METHODS: We measured arterial blood pressure using the LiDCOrapid Continuous Non-invasive Arterial Pressure (CNAP) finger cuff during surgery in patients enrolled in the WHiTE 5 trial randomized to cemented or modern uncemented hip hemiarthroplasty at a single recruiting site. We observed the incidence, timing, and magnitude of haemodynamic instability at key stages of the surgical procedure. RESULTS: We obtained measurements from 56 patients, of whom 46 had complete recordings and were used in the analysis. Modest falls in systolic blood pressure (20% to 30%) occurred in four patients (15%) who received a cemented hemiarthroplasty and one patient (5%) in the uncemented group. The fall in blood pressure occurred either within five minutes of cementing or at final hip reduction. We observed concurrent drops in cardiac output (CO) and stroke volume (SV). CONCLUSION: We observed the presence of two potential periods for haemodynamic instability during hip hemiarthroplasty surgery: the first was within five minutes of cementing the femoral canal and the second after final reduction of the prosthesis (observed in both cemented and uncemented hemiarthroplasty). The falls in blood pressure appeared to be driven by reduced CO and SV.
Do patients with minimally displaced distal radial fractures need a plaster cast?
Traditionally, patients with a fracture of the distal radius are treated in a cast if they do not require surgery. If the fracture requires manipulation, the cast is moulded to hold the reduction and maintain normal anatomical alignment during healing. However, is a cast necessary for patients whose fracture does not require manipulation? Removable splints are an alternative treatment option. Such splints have the advantage that they can be adjusted to improve fit around the wrist as swelling reduces, and can be removed and reapplied for the purpose of washing or, in some cases, exercise. However, evidence for their safety and effectiveness in the management of distal radius fractures is lacking. DRAFT3 is a multicentre randomized non-inferiority trial and economic analysis designed to determine the safety and effectiveness of removable splints as an alternative to casts in the treatment of distal radius fractures that do not require manipulation.
The Skeletal Ciliopathies
Within the broad and growing spectrum of human ciliopathies is a range of linked and overlapping disorders that present with skeletal features. These have been coined the skeletal ciliopathies. The syndromes have, to this point, been largely attributed to alterations in cellular Hedgehog signalling during development. However, a huge surge in fundamental discovery and clinical research has unveiled a plethora of roles for cilia in biology. This implicates a range of molecular and cell processes in the pathogenesis of skeletal ciliopathies. Our understanding of bi-directional interactions between cilia and the extracellular matrix remains in its infancy. The identification of genes and causal mutations defines skeletal ciliopathies. Some of these genes, and the proteins they encode, are now being explored further, by means of cell, animal, and other model approaches, seeking to understand the molecular underpinnings of disease. However, given the relatively recent appreciation of links between cilia biology and human disease, there is much work to be done. This chapter will briefly introduce the primary cilium and its associated ‘ciliome’, before describing the ciliary-associated skeletal disorders and the genes with which they are associated. Where possible, it will expand upon our current mechanistic understanding.
Impact of pandemic service changes on ethnic inequalities in maternal and perinatal outcomes in England: a population-based study.
OBJECTIVE: In the UK and worldwide, there are substantial ethnic inequalities in maternal and perinatal care and outcomes. We aim to assess the impact of the unprecedented change in care provision during the COVID-19 pandemic on inequalities in adverse maternity outcomes. DESIGN: Retrospective cohort study using structured electronic health record data. SETTING: English hospital trusts providing maternity care. PARTICIPANTS: Women giving birth and babies born in the National Health Service (NHS) in England between 1 April 2018 and 31 March 2021, in three time groups: prepandemic, the first pandemic wave (26 March 2020 to 30 June 2020) and second pandemic wave (1 July 2020 to 31 March 2021). Self-reported ethnicity was grouped into White, South-Asian, Black, Mixed and Other. MAIN OUTCOME MEASURES: Composite and component measures of maternal (emergency caesarean section, obstetric anal sphincter injury, hysterectomy, sepsis, anaesthetic complications and prolonged hospital stay) and perinatal (stillbirth, neonatal death, preterm birth, brain injury, small for gestational age and prolonged hospital stay). Poisson regression was used to compare relative risks between different ethnic groups. FINDINGS: 1.54 million maternal and 1.43 million neonatal records were included. The overall incidence of adverse outcomes per 1000 births initially decreased maternal: from 308.0 (95% CI 307.0 to 309.0) to 291.0 (95% CI 311.4 to 314.9) (p<0.001); perinatal: from 133.0 (95% CI 132.3 to 133.7) to 111.9 (95% CI 110.1 to 113.7) (p<0.001)), but then increased in the second pandemic period (maternal: 313.2 (95% CI 311.4 to 314.9) (p<0.001); perinatal 118.9 (95% CI 117.7 to 120.0) (p<0.001)). The risk of adverse outcomes was higher in women and babies from all ethnic minority groups compared with White women in both pandemic periods. Black and South-Asian women and babies were approximately 25% more likely to sustain adverse outcomes. While similar overall changes in adverse outcomes were seen in all groups, existing inequalities were sustained throughout the pandemic periods. INTERPRETATION: Existing inequalities in adverse maternal and perinatal/neonatal outcomes were maintained, not tempered, during the pandemic, despite substantial changes to maternity services and care. Further research on possible interventions to reduce inequality is needed.