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Instrumentation optimisation for unicompartmental knee replacement
The cementless medial Oxford Unicompartmental Knee Replacement (OUKR) has improved outcomes and almost halved revision rates compared to the cemented OUKR at 10 years. However, there is limited understanding of long-term complications of the cementless OUKR beyond 10 years, such as aseptic loosening and bearing fracture, and short-term complications, such as tibial component subsidence (TCS) and tibial periprosthetic fracture (TPF). The aims of this thesis were to investigate poorly understood OUKR complications, understand instrumentation limitations that may contribute to the risk of complications, and to optimise the instruments to minimise the risk of complications. 10-year results of a randomised controlled trial with radiostereometric and radiographic analysis found that cementless fixation is likely to be as good, if not better than cemented fixation in the second decade. Two cemented tibial components with substantial early migration had ongoing migration at 10 years. Cementless OUKRs (1/15) had fewer tibial radiolucent lines compared to cemented (6/14) at 10 years. Bearing fractures, because of excessive polyethylene wear, have been reported with the Phase III OUKR. There is a concern that cementless fixation might be associated with increased wear due to third body debris. The mean linear polyethylene wear of Phase III OUKR (0.06 mm/year) was found to be approximately three times higher than the Phase II wear rate, with no difference in wear rate between cemented and cementless implants. To minimise the risk of bearing fracture in the very long-term, surgeons should position the bearing close to the tibial wall, neutrally align the femoral component, and avoid using the thinnest Size 3 bearings in young patients. A radiographic study of 94 cementless OUKR patients identified five cases (5%) of TCS. No patient, implant, or surgical factors were found to be associated with TCS, likely due to the small number of TCS cases identified. All TCS patients had an acceptable five-year clinical and radiographic outcome, therefore it is recommended that TCS should be treated conservatively. The first surgeon survey to identify limitations of the OUKR instrumentation was conducted. The 106 surgeons who responded were satisfied with most of the OUKR instrumentation. Instruments for patient positioning (36%), tibial resection (51%), femoral preparation (41%), and tibial keel slot preparation (29%) were identified to have limitations that required improvement. Most surgeons (63%) believed that computer assisted surgery would improve the OUKR procedure. The risk of OUKR TPF is higher for cementless OUKRs. Mechanical experiments found that preventing vertical overcut using a prototype resection guide can decrease the risk of TPF. Positioning the component more medially, distally, and valgus was found to increase the risk of TPF in a small tibial model. Preparing a shorter keel slot with a buffer sawblade and rasping the slot ends increased LTF by 11% compared to the standard sawblade without compromising primary fixation. Comparatively, use of a component with a shorter and shallower keel increased LTF by 38%, also without compromising fixation. To minimise the risk of TPF with cementless OUKR it was recommended that the buffer saw and rasp should be adopted clinically until a component with a shorter and shallower keel is available. This thesis improves the understanding of the risk of aseptic loosening, polyethylene wear, bearing fracture, TCS, TPF, and instrumentation limitations from the surgeon’s perspective for the OUKR. It has proposed optimised instruments to minimise the risk of TPF for cementless OUKR and concludes by outlining how these instruments can be introduced clinically to reduce the incidence of TPF.
Impact of COVID-19 Diagnosis on Weight Trajectories of Children in the US National COVID Cohort Collaborative
Background: The COVID-19 pandemic has exacerbated the obesity epidemic, with both adults and children demonstrating rapid weight gain during the pandemic. However, the impact of having a COVID-19 diagnosis on this trend is not known. Methods: Using longitudinal data from January 2019 to June 2023 collected by the US National Institute for Health’s National COVID Cohort Collaborative (N3C), children (age 2-18 years) with positive COVID-19 test results fn = 11,474, 53% male, mean [standard deviation (SD)] age 5.57 [-3.29] years, 54% White, mean [SD] 5.2 [-2.9] BMI observations per participantg were matched with COVID-19-negative children with identical demographic characteristics and similar observation window. We compared BMI percentile trajectories between the COVID-19-positive and COVID-19-negative cohorts, with further evaluation performed on COVID-19-positive patients stratified by hospitalization status. Results: COVID-19-positive patients had a greater increase in %BMIp95 than COVID-19-negative patients (average increase of 2.34 (-7.73) compared to 1.46 (-6.09), p < 0.0005). COVID-19-positive patients gained more weight after their diagnosis of COVID-19 than before. Nonhospitalized children gained more weight than hospitalized children [average increase in %BMIp95 of 2.38 (-7.65) compared to 1.87 (-8.54)]. Mixed-effect regression analyses demonstrated that these associations remained even after adjusting for time, demographics, and baseline %BMIp95. Conclusions: Having a COVID-19 diagnosis was associated with more rapid weight gain, especially after diagnosis and early in the pandemic. Future research should explore the reasons for this association and the implications for future health emergencies.
Refinement of post-COVID condition core symptoms, subtypes, determinants, and health impacts: a cohort study integrating real-world data and patient-reported outcomes.
BACKGROUND: Post-COVID-19 condition (PCC) affects millions of people, and is an essential component of the long-term impact of COVID-19 during the post-pandemic era. Yet, consensus on clinical case definition and core components of PCC remains lacking, affecting our ability to inform research and evidence-based management. Our study aims 1) to identify the most specific symptoms for PCC, and identify clinical subtypes; 2) to evaluate both virus- and host-related determinants of PCC, and 3) assess the impact of PCC on physical and mental health. METHODS: We studied participants from UK Biobank who completed a health and wellbeing survey between June and September 2022. Participants reported the current conditions of the presence, duration, and functional limitations of 45 symptoms, using an online questionnaire designed specifically for COVID-19 research. SARS-CoV-2 infection status and disease history were obtained through linkage to surveillance data and electronic medical records, respectively. Participants reporting symptoms within 30 days after infection (acute phase) were excluded. The most specific PCC symptoms were defined using two criteria: statistical significance (P 5%). Propensity score weighting was used to control for confounding. Subtypes of PCC were then defined based on the specific symptoms among the COVID-19 infected individuals. A multivariable regression was used to study pathogen- and host-related risk factors for PCC, and its impact on 13 physical and 4 mental health patient-reported functional outcomes. FINDINGS: 172,303 participants (mean age 68.9, 57.4% female) were included in the analysis, of whom 43,395 had PCR-confirmed COVID-19. We identified 10 most specific symptoms and classified four PCC subtypes: ENT subtype (30.1%), characterized by alterations in smell, taste, and hearing loss; cardiopulmonary subtype (10.4%), characterized by shortness of breath, postural tachycardia, chest tightness, and chest pressure; neurological subtype (23.5%), characterized by brain fog and difficulty speaking; and general fatigue subtype (38.0%), characterized by mild fatigue. A higher PCC risk was observed for patients with Wild-type variant, multiple infections, and severe acute COVID-19 illness, consistently across the four PCC subtypes. In addition, a range of factors, including socioeconomic deprivation, higher BMI, unhealthy lifestyle, and multiple chronic health conditions, were associated with increased PCC risk, except for age and sex. Conversely, vaccination was associated with a largely reduced PCC risk, particularly for the cardiopulmonary subtypes. Individuals with PCC experienced a much worse physical and mental health. Specifically, the cardiopulmonary subtype had the most pronounced adverse impact on function impairments, followed by neurological, mild fatigue, and ENT subtype. The most affected functions included the ability to concentrate, participate in day-to-day work, and emotional vulnerability to health problems. INTERPRETATION: PCC can be categorized into four distinct subtypes based on ten core symptoms. These subtypes appeared to share a majority of pathogen and host-related risk factors, but their impact on health varied markedly by subtype. Our findings could help refine current guidelines for precise PCC diagnosis and progression, enhance the identification of PCC subgroups for targeted research, and inform evidence-based policy making to tackle this new and debilitating condition. FUNDING: NIHR Senior Research Fellowship (grant SRF-2018-11-ST2-004).
Prevalence and demographics of 331 rare diseases and associated COVID-19-related mortality among 58 million individuals: a nationwide retrospective observational study.
BACKGROUND: The Global Burden of Disease Study has provided key evidence to inform clinicians, researchers, and policy makers across common diseases, but no similar effort with a single-study design exists for hundreds of rare diseases. Consequently, for many rare conditions there is little population-level evidence, including prevalence and clinical vulnerability, resulting in an absence of evidence-based care that was prominent during the COVID-19 pandemic. We aimed to inform rare disease care by providing key descriptors from national data and explore the impact of rare diseases during the COVID-19 pandemic. METHODS: In this nationwide retrospective observational cohort study, we used the electronic health records (EHRs) of more than 58 million people in England, linking nine National Health Service datasets spanning health-care settings for people who were alive on Jan 23, 2020. Starting with all rare diseases listed in Orphanet (an extensive online resource for rare diseases), we quality assured and filtered down to analyse 331 conditions mapped to ICD-10 or Systemized Nomenclature of Medicine-Clinical Terms that were clinically validated in our dataset. For all 331 rare diseases, we calculated population prevalences, analysed patients' clinical and demographic details, and investigated mortality with SARS-CoV-2. We assessed COVID-19-related mortality by comparing cohorts of patients for each rare disease and rare disease category with controls matched for age group, sex, ethnicity, and vaccination status, at a ratio of two controls per individual with a rare disease. FINDINGS: Of 58 162 316 individuals, we identified 894 396 with at least one rare disease and assessed COVID-19-related mortality between Sept 1, 2020, and Nov 30, 2021. We calculated reproducible estimates, adjusted for age and sex, for all 331 rare diseases, including for 186 (56·2%) conditions without existing prevalence estimates in Orphanet. 49 rare diseases were significantly more frequent in female individuals than in male individuals, and 62 were significantly more frequent in male individuals than in female individuals; 47 were significantly more frequent in Asian or British Asian individuals than in White individuals; and 22 were significantly more frequent in Black or Black British individuals than in White individuals. 37 rare diseases were significantly more frequent in the White population compared with either the Black or Asian population. 7965 (0·9%) of 894 396 patients with a rare disease died from COVID-19, compared with 141 287 (0·2%) of 58 162 316 in the full study population. In fully vaccinated individuals, the risk of COVID-19-related mortality was significantly higher for eight rare diseases, with patients with bullous pemphigoid (hazard ratio 8·07, 95% CI 3·01-21·62) being at highest risk. INTERPRETATION: Our study highlights that national-scale EHRs provide a unique resource to estimate detailed prevalence, clinical, and demographic data for rare diseases. Using COVID-19-related mortality analysis, we showed the power of large-scale EHRs in providing insights to inform public health decision making for these often neglected patient populations. FUNDING: British Heart Foundation Data Science Centre, led by Health Data Research UK.
Hearing loss and risk of major osteoporotic fracture: a population-based cohort study in the United Kingdom.
UNLABELLED: Using the UK Clinical Practice Research Datalink, our cohort study matched 237,297 individuals with hearing loss (HL) to 829,431 without HL. The study found an 8-10% higher risk of major osteoporotic fracture in individuals with HL compared to those without. Additionally, within the HL cohort, we identified risk factors for potential inclusion in fracture risk models. PURPOSE: Assess association between hearing loss (HL) and major osteoporotic fracture (MOF; spine, wrist/forearm, shoulder/proximal humerus, hip) in individuals aged ≥ 60 years, and risk factors for MOF in individuals with HL. METHODS: From the UK Clinical Practice Research Datalink, our cohort study matched individuals aged ≥ 60 years diagnosed with HL (READ/ICD-10 codes; 01January2001-31December2021; index event), without secondary osteoporosis causes, with up to five individuals without HL (birth, index year, sex, general practice). Incidence rates and Cox proportional hazard ratios (HL vs. no HL; stratified by low/high fracture risk) were calculated for MOF and hip fracture; multivariate logistic regression assessed risk factors for MOF and hip fracture (HL cohort). RESULTS: A total of 237,297 individuals with HL matched to 829,431 without HL, with a median age of 74 and 72 years, respectively. Compared with those without HL, individuals with HL had greater frailty (severe electronic frailty index, 5.9% vs. 2.7%), higher incidence of prior falls (14.1% vs. 10.6%), longer mean follow-up with higher incidence of MOF and hip fractures (5.1 vs. 4.4 years, 20.1 and 5.32 vs. 16.58 and 4.54 per 1000 person-years, respectively) and higher risk of MOF and hip fracture (adjusted HR, 1.10 and 1.08, respectively). Significant risk factors for MOF and hip fracture included age ≥ 70 years, fracture history, falls, osteoporosis diagnosis, chronic obstructive pulmonary disorder and cardiovascular disease (HL cohort). CONCLUSION: In individuals with HL, we observed an 8-10% higher risk of MOF and hip fracture versus individuals without HL and identified risk factors for potential inclusion in fracture risk models.
Development of Attention-based Prediction Models for All-cause Mortality, Home Care Need, and Nursing Home Admission in Ageing Adults in Spain Using Longitudinal Electronic Health Record Data.
Predicting health-related outcomes can help with proactive healthcare planning and resource management. This is especially important on the older population, an age group growing in the coming decades. Considering longitudinal rather than cross-sectional information from primary care electronic health records (EHRs) can contribute to more informed predictions. In this work, we developed prediction models using longitudinal EHRs to inform resource allocation. In this study, we developed deep-learning-based prognostic models to predict 1-year and 5-year all-cause mortality, nursing home admission, and home care need in people over 65 years old using all the longitudinal information from EHRs. The models included attention mechanisms to increase their transparency. EHRs were drawn from SIDIAP (primary care, Catalonia (Spain)) from 2010-2019. Performance on the test set was compared to that from baseline models using cross-sectional one-year history only. Data from 1,456,052 individuals over 65 years old were considered. Cohen's kappa obtained using longitudinal data was 3.4-fold (1-year all-cause mortality), 10.3-fold (5-year all-cause mortality), 1.1-fold (5-year nursing home admission), and 1.2-fold (5-year home care need) higher than that obtained by the one-year history baseline models. Our models performed better than those not considering longitudinal data, especially when predicting further into the future. However, nursing home admission and home care need in the long term were harder to predict, suggesting their dependence on more abrupt changes. The attention maps helped to understand the predictions, enhancing model transparency. These prediction models can contribute to improve resource allocation in the general population of aging adults.
Time to HIV viral rebound and frequency of post-treatment control after analytical interruption of antiretroviral therapy: an individual data-based meta-analysis of 24 prospective studies.
The only current strategy to test efficacy of novel interventions for sustained HIV control without antiretroviral therapy (ART) among people with HIV (PWH) is through an analytical treatment interruption (ATI). Inclusion of 'placebo' controls in ATIs poses ethical, logistical, and economic challenges. To understand viral dynamics and rates of post-treatment control (PTC) after ATI among PWH receiving either placebo or no intervention, we undertook an individual-participant data meta-analysis. In total, 24 eligible prospective studies with 382 individuals with ≥5 plasma HIV RNA viral loads (pVLs) within the first 84 days post-ATI were included. Early-ART was defined as ART initiation within 6 months of HIV acquisition; others were classified as late-ART or unknown. Median age was 42 years, 91% male, 75% white, 45% received early-ART. Median time to pVL >50, >400, and >10,000 copies/mL was 16 days (interquartile range [IQR]:13-25), 21 (IQR:15-28), and 32 (IQR:20-35), respectively. PTC defined as pVL <50 copies/mL at day 84 occurred in 4% (n = 14) of participants (6% early-ART and 1% late-ART). Sustained PTC of pVL <50 copies/ml after 84 days is rare in PWH, especially in those starting ART late. Our findings inform future interventional HIV cure/remission trials on study size and design.
The in£uence of CD25+ cells on the generation of immunity to tumour cell lines in mice
CD25+ regulatory T cells comprise 5-10% of CD4+ T cells in naive mice and have been shown in several in vivo murine models to prevent the induction of autoimmune disease and in£ammatory disease. Since T cells, which mediate autoimmunity, can through recognition of self-antigens also target tumour cells, it was postulated that CD25+ regulatory cells would also inhibit the generation of immune responses to tumours. Depletion of these cells using CD25-specific monoclonal antibodies has indeed been shown to promote rejection of several transplantable murine tumour cell lines including melanoma, leukaemia and colorectal carcinoma. Results obtained using these models indicate that in the absence of regulatory cells, CD4+ T cells mediate tumour immunity, although the precise mechanisms through which these cells result in tumour rejection have not yet been elucidated. The target antigens recognized by these CD4+ T cells have also not yet been identified. Immunization of mice with tumour cells in the absence of CD25+ regulatory cells does, however, induce immunity against a variety of different tumour cell lines indicating that the target antigen(s) are shared amongst tumours of distinct histological origins. Since CD25+ regulatory cells have been identified in humans, the possibility that the cells inhibit immune responses to shared rejection antigens expressed by human tumours is worthy of investigation.
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.