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First-in-man study of the PSMA Minibody IR800-IAB2M for molecularly targeted intraoperative fluorescence guidance during radical prostatectomy
Abstract Purpose Prostate-specific membrane antigen (PSMA) is increasingly used to image prostate cancer in clinical practice. We sought to develop and test a humanised PSMA minibody IAB2M conjugated to the fluorophore IRDye 800CW-NHS ester in men undergoing robot-assisted laparoscopic radical prostatectomy (RARP) to image prostate cancer cells during surgery. Methods The minibody was evaluated pre-clinically using PSMA positive/negative xenograft models, following which 23 men undergoing RARP between 2018 and 2020 received between 2.5 mg and 20 mg of IR800-IAB2M intravenously, at intervals between 24 h and 17 days prior to surgery. At every step of the procedure, the prostate, pelvic lymph node chains and extra-prostatic surrounding tissue were imaged with a dual Near-infrared (NIR) and white light optical platform for fluorescence in vivo and ex vivo. Histopathological evaluation of intraoperative and postoperative microscopic fluorescence imaging was undertaken for verification. Results Twenty-three patients were evaluated to optimise both the dose of the reagent and the interval between injection and surgery and secure the best possible specificity of fluorescence images. Six cases are presented in detail as exemplars. Overall sensitivity and specificity in detecting non-lymph-node extra-prostatic cancer tissue were 100% and 65%, and 64% and 64% respectively for lymph node positivity. There were no side-effects associated with administration of the reagent. Conclusion Intraoperative imaging of prostate cancer tissue is feasible and safe using IR800-IAB2M. Further evaluation is underway to assess the benefit of using the technique in improving completion of surgical excision during RARP. Registration ISCRCTN10046036: https://www.isrctn.com/ISRCTN10046036.
Sharing is caring? International Society for Pharmacoepidemiology review and recommendations for sharing programming code
Purpose: There is increasing recognition of the importance of transparency and reproducibility in scientific research. This study aimed to quantify the extent to which programming code is publicly shared in pharmacoepidemiology, and to develop a set of recommendations on this topic. Methods: We conducted a literature review identifying all studies published in Pharmacoepidemiology and Drug Safety (PDS) between 2017 and 2022. Data was extracted on the frequency and types of programming code shared, and other key open science practices (clinical codelist sharing, data sharing, study pre-registration, and stated use of reporting guidelines and preprinting). We developed six recommendations for investigators who choose to share code and gathered feedback from members of the International Society for Pharmacoepidemiology (ISPE). Results: Programming code sharing by articles published in PDS ranged from 1.8% in 2017 to 9.5% in 2022. It was more prevalent among articles with a methodological focus, simulation studies, and papers which also shared record-level data. Conclusion: Programming code sharing is rare but increasing in pharmacoepidemiology studies published in PDS. We recommend improved reporting of whether code is shared and how available code can be accessed. When sharing programming code, we recommend the use of permanent digital identifiers, appropriate licenses, and, where possible, adherence to good software practices around the provision of metadata and documentation, computational reproducibility, and data privacy.
T-cell and antibody responses to first BNT162b2 vaccine dose in previously infected and SARS-CoV-2-naive UK health-care workers: a multicentre prospective cohort study.
BACKGROUND: Previous infection with SARS-CoV-2 affects the immune response to the first dose of the SARS-CoV-2 vaccine. We aimed to compare SARS-CoV-2-specific T-cell and antibody responses in health-care workers with and without previous SARS-CoV-2 infection following a single dose of the BNT162b2 (tozinameran; Pfizer-BioNTech) mRNA vaccine. METHODS: We sampled health-care workers enrolled in the PITCH study across four hospital sites in the UK (Oxford, Liverpool, Newcastle, and Sheffield). All health-care workers aged 18 years or older consenting to participate in this prospective cohort study were included, with no exclusion criteria applied. Blood samples were collected where possible before vaccination and 28 (±7) days following one or two doses (given 3-4 weeks apart) of the BNT162b2 vaccine. Previous infection was determined by a documented SARS-CoV-2-positive RT-PCR result or the presence of positive anti-SARS-CoV-2 nucleocapsid antibodies. We measured spike-specific IgG antibodies and quantified T-cell responses by interferon-γ enzyme-linked immunospot assay in all participants where samples were available at the time of analysis, comparing SARS-CoV-2-naive individuals to those with previous infection. FINDINGS: Between Dec 9, 2020, and Feb 9, 2021, 119 SARS-CoV-2-naive and 145 previously infected health-care workers received one dose, and 25 SARS-CoV-2-naive health-care workers received two doses, of the BNT162b2 vaccine. In previously infected health-care workers, the median time from previous infection to vaccination was 268 days (IQR 232-285). At 28 days (IQR 27-33) after a single dose, the spike-specific T-cell response measured in fresh peripheral blood mononuclear cells (PBMCs) was higher in previously infected (n=76) than in infection-naive (n=45) health-care workers (median 284 [IQR 150-461] vs 55 [IQR 24-132] spot-forming units [SFUs] per 106 PBMCs; p<0·0001). With cryopreserved PBMCs, the T-cell response in previously infected individuals (n=52) after one vaccine dose was equivalent to that of infection-naive individuals (n=19) after receiving two vaccine doses (median 152 [IQR 119-275] vs 162 [104-258] SFUs/106 PBMCs; p=1·00). Anti-spike IgG antibody responses following a single dose in 142 previously infected health-care workers (median 270 373 [IQR 203 461-535 188] antibody units [AU] per mL) were higher than in 111 infection-naive health-care workers following one dose (35 001 [17 099-55 341] AU/mL; p<0·0001) and higher than in 25 infection-naive individuals given two doses (180 904 [108 221-242 467] AU/mL; p<0·0001). INTERPRETATION: A single dose of the BNT162b2 vaccine is likely to provide greater protection against SARS-CoV-2 infection in individuals with previous SARS-CoV-2 infection, than in SARS-CoV-2-naive individuals, including against variants of concern. Future studies should determine the additional benefit of a second dose on the magnitude and durability of immune responses in individuals vaccinated following infection, alongside evaluation of the impact of extending the interval between vaccine doses. FUNDING: UK Department of Health and Social Care, and UK Coronavirus Immunology Consortium.
The impact of inversions across 33,924 families with rare disease from a national genome sequencing project.
Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (>50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts.
Pharmacological interventions for early-stage frozen shoulder: a systematic review and network meta-analysis.
OBJECTIVES: To evaluate the efficacy of pharmacological interventions for treating early-stage, pain predominant, adhesive capsulitis, also known as frozen shoulder. METHODS: We performed a systematic review in accordance with PRSIMA guidelines. Searches were conducted on PUBMED, EMBASE and Cochrane Central Register of Controlled Trials on the 24th of February 2022. Outcomes were shoulder pain, shoulder function and range of movement. Synthesis involved both qualitative analysis for all studies and pairwise meta-analyses followed by a network meta-analysis for randomised controlled trials (RCTs). RESULTS: A total of 3,252 articles were found, of which 31 met inclusion criteria, and 22 of these were RCTs. Intraarticular (IA) injection of corticosteroids (8 RCTS, 340 participants) and IA injection of platelet-rich plasma (PRP) (3 RCTs, 177 participants) showed benefit at 12 weeks compared with physical therapy in terms of shoulder pain and function, while oral non-steroidal anti-inflammatories (NSAIDs) (2 RCTs, 44 participants) and IA injection of hyaluronate (2 RCTs, 42 participants) did not show a benefit. Only IA PRP showed benefit over physical therapy for shoulder range of movement. CONCLUSION: These results shows that IA corticosteroids IA PRP injections are beneficial for early-stage frozen shoulder. These findings should be appraised with care considering the risk of bias, heterogeneity, and inconsistency of the included studies. We believe that research focused on early interventions for frozen shoulder could improve patient outcomes and lead to cost-savings derived from avoiding long-term disability. Further well-designed studies comparing with standardised physical therapy or placebo are required to improve evidence to guide management.
Mobility and strength training with and without protein supplements for pre-frail or frail older adults with low protein intake: the Maximising Mobility and Strength Training (MMoST) feasibility randomised controlled trial protocol
Background Frailty is a common syndrome affecting older people and puts them at risk of hospitalisation, needing care or death. First signs of frailty include reduced muscle strength and mobility decline. A key cause of mobility decline as we age is sarcopenia (age related reduction in muscle strength and mass). Poor nutrition contributes to sarcopenia. A shortfall in protein is associated with reduced muscle mass and strength. This may be due to inadequate intake but also because older people have higher protein needs, especially those with multimorbidity. We need to develop effective treatment to reduce or slow the onset of frailty and mobility decline. Exercise is a recommended treatment. Protein supplements to address the shortfall in protein have the potential to enhance the benefit of regular exercise in frail or pre-frail older adults. This has yet to be definitively demonstrated. Aim To establish the feasibility of conducting an RCT evaluating mobility and strength training with or without protein supplements for people over 60 years old who are frail or pre-frail with a low protein intake. Methods A multicentre, parallel, 2-group, feasibility RCT. Participants (recruitment target = 50) with problems walking, low protein intake and classified as frail or pre-frail will be recruited from four NHS Physiotherapy community services. Participants will be randomised (secure computer-generated: 1:1) to receive 24 weeks of mobility and strength training (delivered in 16 group sessions plus home exercises) or 24 weeks of mobility and strength training with daily protein supplements. Primary feasibility objectives are to estimate 1) ability to screen and recruit eligible participants, 2) intervention fidelity, adherence, and tolerance and 3) retention of participants at follow up. Secondary objectives are to 1) test data collection procedures, 2) assess data completeness and 3) confirm sample size calculation for a definitive RCT. Registration ISRCTN Registry (ISRCTN30405954; 18/10/2022).
Trends of use and characterisation of anti-dementia drugs users: a large multinational-network population-based study.
BACKGROUND: An updated time-trend analysis of anti-dementia drugs (ADDs) is lacking. The aim of this study is to assess the incident rate (IR) of ADD in individuals with dementia using real-world data. SETTING: Primary care data (country/database) from the UK/CPRD-GOLD (2007-20), Spain/SIDIAP (2010-20) and the Netherlands/IPCI (2008-20), standardised to a common data model. METHODS: Cohort study. Participants: dementia patients ≥40 years old with ≥1 year of previous data. Follow-up: until the end of the study period, transfer out of the catchment area, death or incident prescription of rivastigmine, galantamine, donepezil or memantine. Other variables: age/sex, type of dementia, comorbidities. Statistics: overall and yearly age/sex IR, with 95% confidence interval, per 100,000 person-years (IR per 105 PY (95%CI)). RESULTS: We identified a total of (incident anti-dementia users/dementia patients) 41,024/110,642 in UK/CPRD-GOLD, 51,667/134,927 in Spain/SIDIAP and 2,088/17,559 in the Netherlands/IPCI.In the UK, IR (per 105 PY (95%CI)) of ADD decreased from 2007 (30,829 (28,891-32,862)) to 2010 (17,793 (17,083-18,524)), then increased up to 2019 (31,601 (30,483 to 32,749)) and decrease in 2020 (24,067 (23,021-25,148)). In Spain, IR (per 105 PY (95%CI)) of ADD decreased by 72% from 2010 (51,003 (49,199-52,855)) to 2020 (14,571 (14,109-15,043)). In the Netherlands, IR (per 105 PY (95%CI)) of ADD decreased by 77% from 2009 (21,151 (14,967-29,031)) to 2020 (4763 (4176-5409)). Subjects aged ≥65-79 years and men (in the UK and the Netherlands) initiated more frequently an ADD. CONCLUSIONS: Treatment of dementia remains highly heterogeneous. Further consensus in the pharmacological management of patients living with dementia is urgently needed.
Proximity proteomics reveals UCH-L1 as an essential regulator of NLRP3-mediated IL-1β production in human macrophages and microglia.
Activation of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome complex is an essential innate immune signaling mechanism. To reveal how human NLRP3 inflammasome assembly and activation are controlled, in particular by components of the ubiquitin system, proximity labeling, affinity purification, and RNAi screening approaches were performed. Our study provides an intricate time-resolved molecular map of different phases of NLRP3 inflammasome activation. Also, we show that ubiquitin C-terminal hydrolase 1 (UCH-L1) interacts with the NACHT domain of NLRP3. Downregulation of UCH-L1 decreases pro-interleukin-1β (IL-1β) levels. UCH-L1 chemical inhibition with small molecules interfered with NLRP3 puncta formation and ASC oligomerization, leading to altered IL-1β cleavage and secretion, particularly in microglia cells, which exhibited elevated UCH-L1 expression as compared to monocytes/macrophages. Altogether, we profiled NLRP3 inflammasome activation dynamics and highlight UCH-L1 as an important modulator of NLRP3-mediated IL-1β production, suggesting that a pharmacological inhibitor of UCH-L1 may decrease inflammation-associated pathologies.
Meniscal Transplant surgery or Optimised Rehabilitation full randomised trial (MeTeOR2): a study protocol.
INTRODUCTION: Pain and disability after meniscectomy can be a substantial lifelong problem. There are few treatment options, especially for young people. Non-surgical management (rehabilitation) is an option but increasingly surgeons are performing meniscal allograft transplants (MATs) for these individuals. However, this is still an uncommon procedure, and availability and usage of MAT vary widely both in the UK and internationally. It is not known which treatment option is the most effective and cost-effective. METHODS AND ANALYSIS: The Meniscal Transplant surgery or Optimised Rehabilitation trial is an international, multicentre, randomised controlled trial. The aim is to compare the clinical and cost effectiveness of MAT versus an optimised package of individualised, progressive, rehabilitation that we have called personalised knee therapy (PKT).Participants will be recruited from sites across the UK, Australia, Canada and Belgium. The planned 144 participants provide at least 90% power to detect a 10-point difference in the Knee injury and Osteoarthritis Outcome Score (KOOS4) at 24-months post randomisation (primary outcome). A prospectively planned economic evaluation will be conducted from a healthcare system and personal social services perspective. Secondary outcome data including health utility, occupational status, sports participation, mental well-being, further treatment, and adverse events will be collected at 3, 6, 12, 18, and 24 months. Analysis will be on an intention-to-treat basis and reported in-line with the Consolidated Standards of Reporting Trials statement. ETHICS AND DISSEMINATION: The trial was approved by the London-Bloomsbury Research Ethics Committee on 19 August 2022 (22/LO/0327) and Northern Sydney Local Health District Human Research Ethics Committee, NSW, Australia on the 13 March 2023 (2022/ETH01890).Trial results will be disseminated via peer-reviewed publications, presentations at international conferences, in lay summaries and using social media as appropriate.This protocol adheres to the recommended Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist. TRIAL REGISTRATION NUMBER: ISRCTN87336549.
Device-Measured Physical Activity in 3506 Individuals with Knee or Hip Arthroplasty.
PURPOSE: Hip and knee arthroplasty aims to reduce joint pain and increase functional mobility in patients with osteoarthritis; however, the degree to which arthroplasty is associated with higher physical activity is unclear. The current study sought to assess the association of hip and knee arthroplasty with objectively measured physical activity. METHODS: This cross-sectional study analyzed wrist-worn accelerometer data collected in 2013-2016 from UK Biobank participants (aged 43-78 yr). Multivariable linear regression was performed to assess step count, cadence, overall acceleration, and activity behaviors between nonarthritic controls, end-stage arthritic, and postoperative cohorts, controlling for demographic and behavioral confounders. From a cohort of 94,707 participants with valid accelerometer wear time and complete self-reported data, electronic health records were used to identify 3506 participants having undergone primary or revision hip or knee arthroplasty and 68,389 nonarthritic controls. RESULTS: End-stage hip or knee arthritis was associated with taking 1129 fewer steps per day (95% confidence interval (CI), 811-1447; P < 0.001) and having 5.8 fewer minutes per day (95% CI, 3.0-8.7; P < 0.001) of moderate-to-vigorous activity compared with nonarthritic controls. Unilateral primary hip and knee arthroplasties were associated with 877 (95% CI, 284-1471; P = 0.004) and 893 (95% CI, 232-1554; P = 0.008) more steps than end-stage osteoarthritic participants, respectively. Postoperative unilateral hip arthroplasty participants demonstrated levels of moderate-to-vigorous physical activity and daily step count equivalent to nonarthritic controls. No difference in physical activity was observed between any cohorts in terms of overall acceleration, or time spent in daily light activity, sedentary behavior, or sleep. CONCLUSIONS: Hip and knee arthroplasties are associated with higher levels of physical activity compared with participants with end-stage arthritis. Unilateral hip arthroplasty patients, in particular, demonstrate equivalence to nonarthritic peers at more than 1 yr after surgery.
Social contact and the perceived impact of social distancing on health outcomes during the COVID-19 pandemic among community dwelling older adults taking part in the OPAL cohort study.
BACKGROUND: During the COVID-19 pandemic, social distancing and reduced social contact may have affected older adults' health. OBJECTIVES: To evaluate the perceived impact of social distancing on older adults' health and explore the association between social contact and health outcomes. DESIGN: Cross-sectional and longitudinal analyses of the OPAL cohort study. SUBJECTS: Community dwelling older adults. METHODS: We sent questionnaires to participants of an existing cohort study (n = 4328). Questions included the amount and type of social contact, and how often they went outside. Participants rated the impact of social distancing on their health. Sociodemographic factors and quality of life were available from previous questionnaires. We examined quality of life prior to and during the pandemic and explored the cross-sectional relationship between social contact and health using logistic regression. RESULTS: There were 3856/4328 (89%) questionnaires returned. EQ-5D scores changed little compared to pre-pandemic scores but 25% of participants reported their overall health had worsened. The telephone was the most used method of contact (78%). Video calls were used least with 35% of participants not using them or having no access to them. 13% of respondents never went outside. Lower levels of contact were associated with increased risk of reporting worse health (Odds ratio (OR) 1.04 (95% CI 1.01-1.08)). Those experiencing financial strain and who spent less time outside experienced the largest increase in risk of reporting perceived worsened overall health. Those reporting a strain to get by financially were 4 times more likely to report worsened health than those who described themselves as quite comfortably off (OR 4.00 (95% CI 1.86-8.16)). Participants who reported never going outside were twice as likely to report worsened health compared to those who went outside daily (OR 2.00 (95% CI 1.57-2.54)). CONCLUSIONS: Less contact with other people was associated with perceived worsening in overall health. Although many older people reported using online technology, such as video calls, a substantial proportion were not using them. Older people facing financial strain were more likely to report worsened health, highlighting the impact of social inequalities during the pandemic. Going outside less was also associated with perceived worsened health.