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Welcome to our viewers from IF: Oxford. We've put all our family friendly resources on the Oxford Biopatch in this blog post. Do let us know if you have a go at the crafting activities described at the end of this page.
Development of a Canadian Guidance for Reporting Real-world Evidence for Regulatory and Health-Technology Assessment (HTA) Decision Making.
Real-world evidence (RWE) can complement and fill knowledge gaps from randomized controlled trials to assist in health-technology assessment (HTA) for regulatory decision-making. However, the generation of RWE is an intricate process with many sequential decision points, and different methods and approaches may impact the quality and reliability of evidence. Standardization and transparency in reporting these decisions is imperative to appraise RWE and incorporate it into HTA decision-making. A partnership between Canadian health system stakeholders, namely Health Canada and Canada's Drug Agency (formerly the Canadian Agency for Drugs and Technologies in Health (CADTH)), was established to develop a guidance for standardization of reporting of RWE for regulatory and HTA decision-making in Canada. In this article, we describe the methods to develop the Guidance for Reporting Real-World Evidence document and checklist for reporting RWE for regulatory and HTA decision-making in Canada. This guidance can be adapted for other jurisdictions and will have future extensions to incorporate emerging issues with RWE and HTA decision-making.
Incidence, Prevalence, and Survival of Prostate Cancer in the UK.
IMPORTANCE: Incidence, prevalence, and survival are pertinent measures to inform the management and provision of prostate cancer care. OBJECTIVE: To calculate the incidence, prevalence, and survival rates for prostate cancer in the UK from 2000 to 2021. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study uses routinely collected primary care data from the UK. Male patients aged 18 years or older with at least 1 year of history registered in Clinical Practice Research Datalink (CPRD) GOLD or Aurum were included. Data were analyzed from January 2023 to March 2024. MAIN OUTCOMES AND MEASURES: Prostate cancer incidence rates (IR), period prevalence (PP), and 1-, 5-, and 10-year survival after diagnosis between 2000 and 2021, stratified by age and calendar years. RESULTS: This study included 64 925 and 133 200 patients with prostate cancer in CPRD GOLD and Aurum, respectively, with a median age of 72 (65-78) years. The overall IR of prostate cancer was 151.7 (95% CI, 150.6 to 152.9) per 100 000 person-years in GOLD to 153.1 (95% CI, 152.3 to 153.9) per 100 000 person-years for Aurum and increased with age. The incidence of prostate cancer increased from 109 per 100 000 person-years in 2000 to 159 per 100 000 person-years in 2021. Peaks of incidence occurred in 2004 and 2018, before a decline in 2020. PP increased 3.5 times over the study period for both databases, from 0.4% in 2000 to 1.4% in 2021. IR and PP were highest in those aged 80 to 89 years. Median (95% CI) survival was similar in both databases (GOLD: 10.9 [95% CI, 10.7-11.1] years and Aurum: 11.1 [95% CI, 11.0-11.2] years). Survival at 1, 5, and 10 years after diagnosis were 93.4% (95% CI, 93.2%-93.6%), 71.8% (95% CI, 71.4%-72.2%), 53.2% (95% CI, 52.6%-53.7%) in GOLD and 93.9% (95% CI, 93.7%-94.0%), 72.7% (95% CI, 72.5%-73.0%), 53.7% (95% CI, 53.3%-54.1%) in AURUM, respectively. Survival increased over time: 1-year survival was 94.8% (95% CI, 94.5%-95.2%) in those diagnosed between 2015 to 2019 compared with 90.8% (95% CI, 90.2%-91.3%) from 2000 to 2004; 5-year survival improved from 65.3% (95% CI, 64.4%-66.3%) from 2000 to 2004 to 75.3% (95% CI, 74.4%-76.3%) in 2015 to 2019. CONCLUSIONS AND RELEVANCE: In this population-based cohort study, incidence and prevalence increased with older age, with high survival rates reflecting a high burden of disease, particularly in the management of cancer survivorship in an aging population. Health care systems should consider this when managing the increasing numbers of people with prevalent prostate cancer.
Decreasing Case Fatality Rates for Patients With Cirrhosis Infected With SARS-CoV-2: A National COVID Cohort Collaborative Study.
BACKGROUND & AIMS: The virulence and severity of SARS-CoV-2 infections have decreased over time in the general population due to vaccinations and improved antiviral treatments. Whether a similar trend has occurred in patients with cirrhosis is unclear. We used the National COVID Cohort Collaborative (N3C) to describe the outcomes over time. METHODS: We utilized the N3C level 3 data set with uncensored dates to identify all patients with chronic liver disease (CLD) with and without cirrhosis who had SARS-CoV-2 infection as of November 2023. We described the observed 30-day case fatality rate (CFR) by month of infection. We used adjusted survival analyses to calculate relative hazard of death by month of infection compared with infection at the onset of the COVID-19 pandemic. RESULTS: We identified 117,811 total patients with CLD infected with SARS-CoV-2 between March 2020 and November 2023: 27,428 (23%) with cirrhosis and 90,383 (77%) without cirrhosis. The observed 30-day CFRs during the entire study period were 1.1% (1016) for patients with CLD without cirrhosis and 6.3% (1732) with cirrhosis. Observed 30-day CFRs by month of infection varied throughout the pandemic and showed a sustained downward trend since 2022. Compared with infection in Quarter 2 of 2020 (at the beginning of the pandemic), the adjusted hazards of death at 30 days for infection in Quarter 3 of 2023 were 0.20 (95% confidence interval [CI], 0.08-0.50) for patients with CLD without cirrhosis and 0.35 (95% CI, 0.18-0.69) for patients with CLD with cirrhosis. CONCLUSIONS: In this N3C study, we found that the observed 30-day CFR decreased progressively for patients with CLD both with and without cirrhosis, consistent with broader trends seen in the general population.
A Case Demonstration of the Open Health Natural Language Processing Toolkit From the National COVID-19 Cohort Collaborative and the Researching COVID to Enhance Recovery Programs for a Natural Language Processing System for COVID-19 or Postacute Sequelae of SARS CoV-2 Infection: Algorithm Development and Validation
Background: A wealth of clinically relevant information is only obtainable within unstructured clinical narratives, leading to great interest in clinical natural language processing (NLP). While a multitude of approaches to NLP exist, current algorithm development approaches have limitations that can slow the development process. These limitations are exacerbated when the task is emergent, as is the case currently for NLP extraction of signs and symptoms of COVID-19 and postacute sequelae of SARS-CoV-2 infection (PASC). Objective: This study aims to highlight the current limitations of existing NLP algorithm development approaches that are exacerbated by NLP tasks surrounding emergent clinical concepts and to illustrate our approach to addressing these issues through the use case of developing an NLP system for the signs and symptoms of COVID-19 and PASC. Methods: We used 2 preexisting studies on PASC as a baseline to determine a set of concepts that should be extracted by NLP. This concept list was then used in conjunction with the Unified Medical Language System to autonomously generate an expanded lexicon to weakly annotate a training set, which was then reviewed by a human expert to generate a fine-tuned NLP algorithm. The annotations from a fully human-annotated test set were then compared with NLP results from the fine-tuned algorithm. The NLP algorithm was then deployed to 10 additional sites that were also running our NLP infrastructure. Of these 10 sites, 5 were used to conduct a federated evaluation of the NLP algorithm. Results: An NLP algorithm consisting of 12,234 unique normalized text strings corresponding to 2366 unique concepts was developed to extract COVID-19 or PASC signs and symptoms. An unweighted mean dictionary coverage of 77.8% was found for the 5 sites. Conclusions: The evolutionary and time-critical nature of the PASC NLP task significantly complicates existing approaches to NLP algorithm development. In this work, we present a hybrid approach using the Open Health Natural Language Processing Toolkit aimed at addressing these needs with a dictionary-based weak labeling step that minimizes the need for additional expert annotation while still preserving the fine-tuning capabilities of expert involvement.
Associations of County-Level Social Determinants of Health with COVID-19 Related Hospitalization Among People with HIV: A Retrospective Analysis of the U.S. National COVID Cohort Collaborative (N3C)
Individually, the COVID-19 and HIV pandemics have differentially impacted minoritized groups due to the role of social determinants of health (SDoH) in the U.S. Little is known how the collision of these two pandemics may have exacerbated adverse health outcomes. We evaluated county-level SDoH and associations with hospitalization after a COVID-19 diagnosis among people with (PWH) and without HIV (PWOH) by racial/ethnic groups. We used the U.S. National COVID Cohort Collaborative (January 2020-November 2023), a nationally-sampled electronic health record repository, to identify adults who were diagnosed with COVID-19 with HIV (n = 22,491) and without HIV (n = 2,220,660). We aggregated SDoH measures at the county-level and categorized racial/ethnic groups as Non-Hispanic (NH) White, NH-Black, Hispanic/Latinx, NH-Asian and Pacific Islander (AAPI), and NH-American Indian or Alaskan Native (AIAN). To estimate associations of county-level SDoH with hospitalization after a COVID-19 diagnosis, we used multilevel, multivariable logistic regressions, calculating adjusted relative risks (aRR) with 95% confidence intervals (95% CI). COVID-19 related hospitalization occurred among 11% of PWH and 7% of PWOH, with the highest proportion among NH-Black PWH (15%). In evaluating county-level SDoH among PWH, we found higher average household size was associated with lower risk of COVID-19 related hospitalization across racial/ethnic groups. Higher mean commute time (aRR: 1.76; 95% CI 1.10–2.62) and higher proportion of adults without health insurance (aRR: 1.40; 95% CI 1.04–1.84) was associated with a higher risk of COVID-19 hospitalization among NH-Black PWH, however, NH-Black PWOH did not demonstrate these associations. Differences by race and ethnicity exist in associations of adverse county-level SDoH with COVID-19 outcomes among people with and without HIV in the U.S.
Identification of high-performing antibodies for the reliable detection of Tau proteoforms by Western blotting and immunohistochemistry.
Antibodies are essential research tools whose performance directly impacts research conclusions and reproducibility. Owing to its central role in Alzheimer's disease and other dementias, hundreds of distinct antibody clones have been developed against the microtubule-associated protein Tau and its multiple proteoforms. Despite this breadth of offer, limited understanding of their performance and poor antibody selectivity have hindered research progress. Here, we validate a large panel of Tau antibodies by Western blot (79 reagents) and immunohistochemistry (35 reagents). We address the reagents' ability to detect the target proteoform, selectivity, the impact of protein phosphorylation on antibody binding and performance in human brain samples. While most antibodies detected Tau at high levels, many failed to detect it at lower, endogenous levels. By WB, non-selective binding to other proteins affected over half of the antibodies tested, with several cross-reacting with the related MAP2 protein, whereas the "oligomeric Tau" T22 antibody reacted with monomeric Tau by WB, thus calling into question its specificity to Tau oligomers. Despite the presumption that "total" Tau antibodies are agnostic to post-translational modifications, we found that phosphorylation partially inhibits binding for many such antibodies, including the popular Tau-5 clone. We further combine high-sensitivity reagents, mass-spectrometry proteomics and cDNA sequencing to demonstrate that presumptive Tau "knockout" human cells continue to express residual protein arising through exon skipping, providing evidence of previously unappreciated gene plasticity. Finally, probing of human brain samples with a large panel of antibodies revealed the presence of C-term-truncated versions of all main Tau brain isoforms in both control and tauopathy donors. Ultimately, we identify a validated panel of Tau antibodies that can be employed in Western blotting and/or immunohistochemistry to reliably detect even low levels of Tau expression with high selectivity. This work represents an extensive resource that will enable the re-interpretation of published data, improve reproducibility in Tau research, and overall accelerate scientific progress.
The circulating methylome in childhood-onset inflammatory bowel disease.
The genetic contribution to inflammatory bowel disease (IBD) encompassing both Crohn's disease (CD) and ulcerative colitis (UC), accounts for around 20% of disease variance, highlighting the need to characterise environmental and epigenetic influences. Recently considerable progress has been made in characterising the adult methylome, in epigenome-wide association studies. We report detailed analysis of the circulating methylome in 86 patients with childhood-onset CD,UC and 30 controls using the Illumina Infinium Human MethylationEPIC platform. We derive and validate a 4-probe methylation biomarker (RPS6KA2, VMP1, CFI and ARHGEF3), with specificity and high diagnostic accuracy for paediatric IBD in UK and North American cohorts (AUC 0.90-0.94). Significant epigenetic age acceleration is present at diagnosis, with the greatest observed in CD patients. Cis-MeQTL analysis identifies genetic determinants underlying epigenetic alterations notably within the HLA 6p22.1-p21.33 region. Passive smoking exposure is associated with the development of UC rather than CD contrary to previous findings. These data provide new insights into epigenetic alterations in IBD and illustrate the reproducibility and translational potential of epigenome-wide association studies in complex diseases.
Timing Of Primary Surgery for cleft palate (TOPS): protocol for a randomised trial of palate surgery at 6 months versus 12 months of age.
INTRODUCTION: Cleft palate is among the most common birth abnormalities. The success of primary surgery in the early months of life is crucial for successful feeding, speech, hearing, dental development and facial growth. Over recent decades, age at palatal surgery in infancy has reduced. This has led to palatal closure in one-stage procedures being carried out around the age of 12 months, but in some cases as early as 6 months. The primary objective of the Timing Of Primary Surgery for Cleft Palate (TOPS)trial is to determine whether surgery for cleft palate performed at 6 or 12 months of age is most beneficial for speech outcomes. METHODS AND ANALYSIS: Infants with a diagnosis of non-syndromic isolated cleft palate will be randomised to receive standardised primary surgery (Sommerlad technique) for closure of the cleft at either 6 months or 12 months, corrected for gestational age. The primary outcome will be perceived insufficient velopharyngeal function at 5 years of age. Secondary outcomes measured across 12 months, 3 years and 5 years will include growth, safety of the procedure, dentofacial development, speech, hearing level and middle ear function. Video and audio recordings of speech will be collected in a standardised age-appropriate manner and analysed independently by multiple speech and language therapists. The trial aims to recruit and follow-up 300 participants per arm. Data will be analysed according to the intention-to-treat principle using a 5% significance level. All analyses will be prespecified within a full and detailed statistical analysis plan. ETHICS AND DISSEMINATION: Ethical approval has been sought in each participating country according to country-specific procedures. Trial results will be presented at conferences, published in peer-reviewed journals and disseminated through relevant patient support groups. TRIAL REGISTRATION NUMBER: NCT00993551; Pre-results.
Intramedullary nailing of tibial non-unions using the suprapatellar approach: a case series
Background: A number of treatment options are available for diaphyseal non-unions of the tibia, including intramedullary (IM) nailing. An infrapatellar entry point with the knee in deep flexion can make this procedure challenging, especially with associated deformity or an obliterated canal. The suprapatellar approach allows nail insertion with the knee extended, which facilitates correction of malalignment in the sagittal and coronal planes. The aim of our study was to review the outcome of diaphyseal tibial non-unions, treated with an intramedullary nail, using the suprapatellar approach. Method: We retrospectively reviewed consecutive cases with non-union of the tibial shaft, treated with a suprapatellar entry nail between May 2016 and January 2018. Patients who were previously managed with a nail or who had active sepsis were excluded. The rate and time to union, as well as complications were assessed. Results: Thirteen cases were included and followed up until union at a mean of 5.8 months. All were performed percutaneously, without opening of the non-union site. Two patients developed complications, although bony union was still achieved. Conclusion: A suprapatellar entry tibial nail is an acceptable treatment option for tibial non-unions not previously treated with a nail.
Correlation of the squat-and-smile test against other patient-reported outcome scores in knee pathology
Background The use of patient-reported outcome measures (PROMs) for knee pathology may be affected by socioeconomic factors, language barriers and time constraints in busy outpatient clinics. The squat-and-smile test (SST) is an example of such a test that has previously been validated for femur fractures. The aim of this study was to validate the SST against other PROMs in patients with knee pathology. Methods Patients presenting to a subspecialist knee clinic in a large hospital in sub-Saharan Africa were approached to participate. They were asked to squat and the depth of the squat as well as the need to support themselves were classified into four categories. To describe their pain, participants also selected one of three smiley faces (unhappy, neutral, smiling). These test scores were correlated to the patient’s Knee injury and Osteoarthritis Outcome Score (KOOS), Tegner Lysholm score and EQ-5D scores. Results Seventy patients (median age 53.4 years) were included. The squat depth correlated moderately with the KOOS score (r=0.56) and poorly with the EQ-5D and Lysholm scores (r=0.46; r=0.43). The need for squat support had poor correlations with the KOOS, EQ-5D and Lysholm scores (r=0.29; r=0.31; r=0.31), as did the smiley face component (r=0.40; r=0.32; r=0.30). Conclusion For patients with knee pathology, the squat depth correlates moderately with other PROMs. It could therefore be used in settings for which conventional PROMs have limited application. Support needed to squat, and a visual analogue scale of smiley faces, had poor correlation when compared to other knee PROMs and should not be used for the assessment of knee pathology.
Neurocardiology: translational advancements and potential.
In our original white paper published in the The Journal of Physiology in 2016, we set out our knowledge of the structural and functional organization of cardiac autonomic control, how it remodels during disease, and approaches to exploit such knowledge for autonomic regulation therapy. The aim of this update is to build on this original blueprint, highlighting the significant progress which has been made in the field since and major challenges and opportunities that exist with regard to translation. Imbalances in autonomic responses, while beneficial in the short term, ultimately contribute to the evolution of cardiac pathology. As our understanding emerges of where and how to target in terms of actuators (including the heart and intracardiac nervous system (ICNS), stellate ganglia, dorsal root ganglia (DRG), vagus nerve, brainstem, and even higher centres), there is also a need to develop sensor technology to respond to appropriate biomarkers (electrophysiological, mechanical, and molecular) such that closed-loop autonomic regulation therapies can evolve. The goal is to work with endogenous control systems, rather than in opposition to them, to improve outcomes.
Microbiology testing capacity and antimicrobial drug resistance in surgical-site infections: a post-hoc, prospective, secondary analysis of the FALCON randomised trial in seven low-income and middle-income countries.
BACKGROUND: Surgical-site infection (SSI) is one of the most common health-care-associated infections, substantially contributing to antibiotic use. Targeted antibiotic prophylaxis to prevent SSIs and effective treatment are crucial to controlling antimicrobial resistance (AMR). This study aimed to describe the testing capacity and multidrug resistance (MDR) of SSI microorganisms in low-income and middle-income countries (LMICs). METHODS: This analysis included patients undergoing abdominal surgery in seven LMICs (Benin, Ghana, India, Mexico, Nigeria, Rwanda, and South Africa) as part of the FALCON randomised controlled trial. Wound swabs were collected from patients diagnosed with SSI, as per US Centers for Disease Control and Prevention (CDC) definition. Data on microorganism species and MDR, as per CDC and European Centre for Disease Prevention and Control definitions, were analysed alongside hospital-level data on local microbiological practices. An adjusted analysis was performed to identify perioperative factors associated with MDR. Testing capacity was assessed by the completion of swab testing in positively diagnosed SSIs. FINDINGS: Between Dec 10, 2018, and Sept 7, 2020, 5788 patients were recruited to the FALCON trial. 1163 patients were diagnosed with an SSI, of whom 905 (77·8%) received prophylactic antibiotics before surgery. In patients with SSIs, 935 of 1163 (80·4%) did not have a wound swab; 195 were from hospitals not performing swabs (15 hospitals) and 740 were from hospitals with capacity but no swab performed (35 hospitals). Of 228 patients swabbed, 200 (88·5%) had microorganisms detected. Escherichia coli (89 of 200, 37·9%) was the most common microorganism and 116 of 200 (58·0%) patients were not covered by the perioperative prophylactic antibiotic. MDR was found in 102 of 147 (69·4%) patients for whom data were available to determine MDR status. Adjusted analysis found that appropriate prophylactic antibiotic coverage (adjusted odds ratio 0·43, 95% CI 0·19-0·96) and regular availability of infection control teams (0·32, 0·11-0·93) were associated with a significant reduction in MDR. INTERPRETATION: Targeted perioperative antibiotic prophylaxis during contaminated abdominal surgery is insufficient in LMICs, with very few SSI organisms undergoing formal diagnosis. Expansion of testing capacity, development of local guidelines, and implementation of infection control teams could support the prevention of SSI through directed antibiotic prophylaxis, subsequently reducing the burden of MDR. FUNDING: National Institute for Health and Care Research. TRANSLATIONS: For the French and Spanish translations of the abstract see Supplementary Materials section.
Optimal metabolite transport in hollow fibre membrane bioreactors
Hollow fibre membrane bioreactors (HFMBs) provide a fast and efficient method for engineering functional tissue for use in medical treatments. Flow is utilised to overcome mass transport limitations by perfusing nutrient-rich culture medium through the fibre lumen, which can then transport along the fibre lumen or across the porous membrane wall. Cells seeded at the outer membrane wall consume the nutrient and subsequently produce waste metabolites, which are transported away through an external extra-capillary space (ECS) along with excess nutrient. We present and investigate a 2D axisymmetric model for fluid flow and solute transport through a single fibre bioreactor configuration, with cells seeded to the external fibre wall. Fluid flow is modelled by steady lubrication and Darcy equations, which are coupled to the solute transport problem modelled by a system of advection-diffusion equations, supplemented with a reaction term to model the cell layer. Our model analysis reveals how spatially varying wall permeability distributions can be utilised to provide uniform nutrient delivery to a spatially uniform, homogeneous cell population. We also reveal how maximising the transmural pressure drop across the membrane wall is the dominant mechanism for waste removal rather than traditional experimental methods of flushing the ECS.
Synthesis, Characterization and Application of Advanced Antimicrobial Electrospun Polymers
The aim of this work was to synthesize, characterize and apply advanced antimicrobial biocompatible electrospun polymers suitable for medical implants for surgical repairs. Injuries to the musculoskeletal system often necessitate surgical repair, but current treatments can still lead to high failure rates, such as 40% for the repair of rotator cuff tears. Therefore, there is an urgent need for the development of new biocompatible materials that can effectively support the repair of damaged tissues. Additionally, infections acquired during hospitalization, particularly those caused by antibiotic-resistant bacteria, result in more fatalities than AIDS, tuberculosis, and viral hepatitis combined. This underscores the critical necessity for the advancement of antimicrobial implants with specialized coatings capable of combating Methicillin-resistant Staphylococcus aureus (MRSA) and Methicillin-sensitive Staphylococcus aureus (MSSA), two strains notoriously known for their antibiotic resistance. Therefore, we developed an antimicrobial coating incorporating nanoparticle mixtures using the sol-gel process and applied it to electrospun polycaprolactone (PCL) filaments, followed by thorough characterization by using spectroscopic (FTIR, Raman, NMR) microscopic (SEM and SEM-EDX), and tensile test. The results have shown that the integration of electro-spinning technology for yarn production, coupled with surface modification techniques, holds significant potential for creating antimicrobial materials suitable for medical implants for surgical repairs.