Transition to invasive breast cancer is associated with progressive changes in the structure and composition of tumor stroma.

Ductal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor to invasive breast cancer (IBC). To understand the changes in the tumor microenvironment (TME) accompanying transition to IBC, we used multiplexed ion beam imaging by time of flight (MIBI-TOF) and a 37-plex antibody staining panel to interrogate 79 clinically annotated surgical resections using machine learning tools for cell segmentation, pixel-based clustering, and object morphometrics. Comparison of normal breast with patient-matched DCIS and IBC revealed coordinated transitions between four TME states that were delineated based on the location and function of myoepithelium, fibroblasts, and immune cells. Surprisingly, myoepithelial disruption was more advanced in DCIS patients that did not develop IBC, suggesting this process could be protective against recurrence. Taken together, this HTAN Breast PreCancer Atlas study offers insight into drivers of IBC relapse and emphasizes the importance of the TME in regulating these processes.

The Human Tumor Atlas Network: Charting Tumor Transitions across Space and Time at Single-Cell Resolution.

Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.

A Structured Tumor-Immune Microenvironment in Triple Negative Breast Cancer Revealed by Multiplexed Ion Beam Imaging.

The immune system is critical in modulating cancer progression, but knowledge of immune composition, phenotype, and interactions with tumor is limited. We used multiplexed ion beam imaging by time-of-flight (MIBI-TOF) to simultaneously quantify in situ expression of 36 proteins covering identity, function, and immune regulation at sub-cellular resolution in 41 triple-negative breast cancer patients. Multi-step processing, including deep-learning-based segmentation, revealed variability in the composition of tumor-immune populations across individuals, reconciled by overall immune infiltration and enriched co-occurrence of immune subpopulations and checkpoint expression. Spatial enrichment analysis showed immune mixed and compartmentalized tumors, coinciding with expression of PD1, PD-L1, and IDO in a cell-type- and location-specific manner. Ordered immune structures along the tumor-immune border were associated with compartmentalization and linked to survival. These data demonstrate organization in the tumor-immune microenvironment that is structured in cellular composition, spatial arrangement, and regulatory-protein expression and provide a framework to apply multiplexed imaging to immune oncology.

Acinar cell clonal expansion in pancreas homeostasis and carcinogenesis.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer deaths worldwide1. Studies in human tissues and in mouse models have suggested that for many cancers, stem cells sustain early mutations driving tumour development2,3. For the pancreas, however, mechanisms underlying cellular renewal and initiation of PDAC remain unresolved. Here, using lineage tracing from the endogenous telomerase reverse transcriptase (Tert) locus, we identify a rare TERT-positive subpopulation of pancreatic acinar cells dispersed throughout the exocrine compartment. During homeostasis, these TERThigh acinar cells renew the pancreas by forming expanding clones of acinar cells, whereas randomly marked acinar cells do not form these clones. Specific expression of mutant Kras in TERThigh acinar cells accelerates acinar clone formation and causes transdifferentiation to ductal pre-invasive pancreatic intraepithelial neoplasms by upregulating Ras-MAPK signalling and activating the downstream kinase ERK (phospho-ERK). In resected human pancreatic neoplasms, we find that foci of phospho-ERK-positive acinar cells are common and frequently contain activating KRAS mutations, suggesting that these acinar regions represent an early cancer precursor lesion. These data support a model in which rare TERThigh acinar cells may sustain KRAS mutations, driving acinar cell expansion and creating a field of aberrant cells initiating pancreatic tumorigenesis.

Causally estimating the effect of YouTube's recommender system using counterfactual bots.

In recent years, critics of online platforms have raised concerns about the ability of recommendation algorithms to amplify problematic content, with potentially radicalizing consequences. However, attempts to evaluate the effect of recommenders have suffered from a lack of appropriate counterfactuals-what a user would have viewed in the absence of algorithmic recommendations-and hence cannot disentangle the effects of the algorithm from a user's intentions. Here we propose a method that we call "counterfactual bots" to causally estimate the role of algorithmic recommendations on the consumption of highly partisan content on YouTube. By comparing bots that replicate real users' consumption patterns with "counterfactual" bots that follow rule-based trajectories, we show that, on average, relying exclusively on the YouTube recommender results in less partisan consumption, where the effect is most pronounced for heavy partisan consumers. Following a similar method, we also show that if partisan consumers switch to moderate content, YouTube's sidebar recommender "forgets" their partisan preference within roughly 30 videos regardless of their prior history, while homepage recommendations shift more gradually toward moderate content. Overall, our findings indicate that, at least since the algorithm changes that YouTube implemented in 2019, individual consumption patterns mostly reflect individual preferences, where algorithmic recommendations play, if anything, a moderating role.

Integrating genomic features for non-invasive early lung cancer detection.

Radiologic screening of high-risk adults reduces lung-cancer-related mortality1,2; however, a small minority of eligible individuals undergo such screening in the United States3,4. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.

Novel Irritable Bowel Syndrome Subgroups are Reproducible in the Global Adult Population.

BACKGROUND & AIMS: Current classification systems for irritable bowel syndrome (IBS) based on bowel habit do not consider psychological impact. We validated a classification model in a UK population with confirmed IBS, using latent class analysis, incorporating psychological factors. We applied this model in the Rome Foundation Global Epidemiological Survey (RFGES), assessing impact of IBS on the individual and the health care system, and examining reproducibility. METHODS: We applied our model to 2195 individuals in the RFGES with Rome IV-defined IBS. As described previously, we identified 7 clusters, based on gastrointestinal symptom severity and psychological burden. We assessed demographics, health care-seeking, symptom severity, and quality of life in each. We also used the RFGES to derive a new model, examining whether the broader concepts of our original model were replicated, in terms of breakdown and characteristics of identified clusters. RESULTS: All 7 clusters were identified. Those in clusters with highest psychological burden, and particularly cluster 6 with high overall gastrointestinal symptom severity, were more often female, exhibited higher levels of health care-seeking, were more likely to have undergone previous abdominal surgeries, and had higher symptom severity and lower quality of life (P < .001 for trend for all). When deriving a new model, the best solution consisted of 10 clusters, although at least 2 seemed to be duplicates, and almost all mapped on to the previous clusters. CONCLUSIONS: Even in the community, our original clusters derived from patients with physician-confirmed IBS identified groups of individuals with significantly higher rates of health care-seeking and abdominal surgery, more severe symptoms, and impairments in quality of life.

The cost-effectiveness of procalcitonin for guiding antibiotic prescribing in individuals hospitalized with COVID-19: part of the PEACH study.

BACKGROUND: Many hospitals introduced procalcitonin (PCT) testing to help diagnose bacterial coinfection in individuals with COVID-19, and guide antibiotic decision-making during the COVID-19 pandemic in the UK. OBJECTIVES: Evaluating cost-effectiveness of using PCT to guide antibiotic decisions in individuals hospitalized with COVID-19, as part of a wider research programme. METHODS: Retrospective individual-level data on patients hospitalized with COVID-19 were collected from 11 NHS acute hospital Trusts and Health Boards from England and Wales, which varied in their use of baseline PCT testing during the first COVID-19 pandemic wave. A matched analysis (part of a wider analysis reported elsewhere) created groups of patients whose PCT was/was not tested at baseline. A model was created with combined decision tree/Markov phases, parameterized with quality-of-life/unit cost estimates from the literature, and used to estimate costs and quality-adjusted life years (QALYs). Cost-effectiveness was judged at a £20 000/QALY threshold. Uncertainty was characterized using bootstrapping. RESULTS: People who had baseline PCT testing had shorter general ward/ICU stays and spent less time on antibiotics, though with overlap between the groups' 95% CIs. Those with baseline PCT testing accrued more QALYs (8.76 versus 8.62) and lower costs (£9830 versus £10 700). The point estimate was baseline PCT testing being dominant over no baseline testing, though with uncertainty: the probability of cost-effectiveness was 0.579 with a 1 year horizon and 0.872 with a lifetime horizon. CONCLUSIONS: Using PCT to guide antibiotic therapy in individuals hospitalized with COVID-19 is more likely to be cost-effective than not, albeit with uncertainty.

Cell volume expansion and local contractility drive collective invasion of the basement membrane in breast cancer.

Breast cancer becomes invasive when carcinoma cells invade through the basement membrane (BM)-a nanoporous layer of matrix that physically separates the primary tumour from the stroma. Single cells can invade through nanoporous three-dimensional matrices due to protease-mediated degradation or force-mediated widening of pores via invadopodial protrusions. However, how multiple cells collectively invade through the physiological BM, as they do during breast cancer progression, remains unclear. Here we developed a three-dimensional in vitro model of collective invasion of the BM during breast cancer. We show that cells utilize both proteases and forces-but not invadopodia-to breach the BM. Forces are generated from a combination of global cell volume expansion, which stretches the BM, and local contractile forces that act in the plane of the BM to breach it, allowing invasion. These results uncover a mechanism by which cells collectively interact to overcome a critical barrier to metastasis.

Demographic and clinical characteristics associated with advanced stage colorectal cancer: a registry-based cohort study in Saudi Arabia.

BACKGROUND: In Saudi Arabia, approximately one-third of colorectal cancer (CRC) patients are diagnosed at an advanced stage. Late diagnosis is often associated with a worse prognosis. Understanding the risk factors for late-stage presentation of CRC is crucial for developing targeted interventions enabling earlier detection and improved patient outcomes. METHODS: We conducted a retrospective cohort study on 17,541 CRC patients from the Saudi Cancer Registry (1997-2017). We defined distant CRCs as late-stage and localized and regional CRCs as early-stage. To assess risk factors for late-stage CRC, we first used multivariable logistic regression, then developed a decision tree to segment regions by late-stage CRC risk, and finally used stratified logistic regression models to examine geographical and sex variations in risk factors. RESULTS: Of all cases, 29% had a late-stage diagnosis, and 71% had early-stage CRC. Young (< 50 years) and unmarried women had an increased risk of late-stage CRC, overall and in some regions. Regional risk variations by sex were observed. Sex-related differences in late-stage rectosigmoid cancer risk were observed in specific regions but not in the overall population. Patients diagnosed after 2001 had increased risks of late-stage presentation. CONCLUSION: Our study identified risk factors for late-stage CRC that can guide targeted early detection efforts. Further research is warranted to fully understand these relationships and develop and evaluate effective prevention strategies.

Development and external validation of the eFalls tool: a multivariable prediction model for the risk of ED attendance or hospitalisation with a fall or fracture in older adults.

BACKGROUND: Falls are common in older adults and can devastate personal independence through injury such as fracture and fear of future falls. Methods to identify people for falls prevention interventions are currently limited, with high risks of bias in published prediction models. We have developed and externally validated the eFalls prediction model using routinely collected primary care electronic health records (EHR) to predict risk of emergency department attendance/hospitalisation with fall or fracture within 1 year. METHODS: Data comprised two independent, retrospective cohorts of adults aged ≥65 years: the population of Wales, from the Secure Anonymised Information Linkage Databank (model development); the population of Bradford and Airedale, England, from Connected Bradford (external validation). Predictors included electronic frailty index components, supplemented with variables informed by literature reviews and clinical expertise. Fall/fracture risk was modelled using multivariable logistic regression with a Least Absolute Shrinkage and Selection Operator penalty. Predictive performance was assessed through calibration, discrimination and clinical utility. Apparent, internal-external cross-validation and external validation performance were assessed across general practices and in clinically relevant subgroups. RESULTS: The model's discrimination performance (c-statistic) was 0.72 (95% confidence interval, CI: 0.68 to 0.76) on internal-external cross-validation and 0.82 (95% CI: 0.80 to 0.83) on external validation. Calibration was variable across practices, with some over-prediction in the validation population (calibration-in-the-large, -0.87; 95% CI: -0.96 to -0.78). Clinical utility on external validation was improved after recalibration. CONCLUSION: The eFalls prediction model shows good performance and could support proactive stratification for falls prevention services if appropriately embedded into primary care EHR systems.

Postmortem memory of public figures in news and social media.

Deceased public figures are often said to live on in collective memory. We quantify this phenomenon by tracking mentions of 2,362 public figures in English-language online news and social media (Twitter) 1 y before and after death. We measure the sharp spike and rapid decay of attention following death and model collective memory as a composition of communicative and cultural memory. Clustering reveals four patterns of postmortem memory, and regression analysis shows that boosts in media attention are largest for premortem popular anglophones who died a young, unnatural death; that long-term boosts are smallest for leaders and largest for artists; and that, while both the news and Twitter are triggered by young and unnatural deaths, the news additionally curates collective memory when old persons or leaders die. Overall, we illuminate the age-old question of who is remembered by society, and the distinct roles of news and social media in collective memory formation.

Systematic Review and Meta-Analysis of Studies Comparing the Rate of Post-operative Periprosthetic Fracture Following Hip Arthroplasty With a Polished Taper Slip versus Composite Beam Stem.

BACKGROUND: We compared the incidence of postoperative periprosthetic femoral fractures (POPFF) following hip arthroplasty with either a cemented polished taper slip (PTS) stem or a cemented composite beam (CB) stem in comparative studies. METHODS: A systematic review of comparative studies, written in English and published in peer-reviewed journals since the year 2000, was conducted. Study quality was assessed using the Newcastle-Ottawa scale.The overall study qualities were good. There were 913,021 patients from 18 cohorts included in the meta-analysis. There were 294,540 patients who received a CB stem and 618,481 received a PTS stem. Cohorts were classified as high- or low-risk for POPFF based on patient risk factors. A metanalysis was performed using a random effects model, and the relative incidence with 95% confidence intervals (CIs) was reported. RESULTS: The patients at low risk of POPFF had an incidence rate ratio of 3.14 (CI: 2.48, 3.98) for the PTS group versus the CB group. Whereas, the patients at high risk of POPFF had an incidence rate ratio of 9.87 (CI: 3.63, 26.80) for the PTS group versus the CB group. CONCLUSIONS: The risk of POPFF is lower when hip arthroplasty was performed using a CB stem versus a PTS stem. This protective effect was greatest in patients who had a higher risk of POPFF. Surgeons should consider the effect of cemented stem choice on the risk of subsequent periprosthetic femur fracture, particularly in frail or elderly patients who are at a higher risk of postoperative periprosthetic femoral fracture.

Exploring structure/property relationships to health and environmental hazards of polymeric polyisocyanate prepolymer substances-3. Aquatic exposure and hazard of aliphatic diisocyanate-based prepolymers.

The water extractability and acute aquatic toxicity of seven aliphatic diisocyanate-based prepolymer substances were investigated to determine if lesser reactivity of the aliphatic isocyanate groups, as well as increased ionization potential of the expected (aliphatic amine-terminated) polymeric hydrolysis products, would influence their aquatic behavior compared to that of previously investigated aromatic diisocyanate-based prepolymers. At loading rates of 100 and 1,000 mg/L, only the substances having log Kow ≤9 exhibited more than 1% extractability in water, and a maximum of 66% water extractability was determined for a prepolymer having log Kow = 2.2. For the more hydrophobic prepolymer substances (log Kow values from 18-37), water extractability was negligible. High-resolution mass spectrometric analyses were performed on the water-accommodated fractions (WAF) of the prepolymers, which indicated the occurrence of primary aliphatic amine-terminated polymer species having backbones and functional group equivalent weights aligned to those of the parent prepolymers. Measurements of reduced surface tension and presence of suspended micelles in the WAFs further supported the occurrence of these surface-active cationic polymer species as hydrolysis products of the prepolymers. Despite these characteristics, the water-extractable hydrolysis products were practically non-toxic to Daphnia magna. All of the substances tested exhibited 48-h EL50 values of >1,000 mg/L, with one exception of EL50 = 157 mg/L. The results from this investigation support a grouping of the aliphatic diisocyanate-based prepolymers as a class of water-reactive polymer substances having predictable aquatic exposure and a uniformly low hazard potential, consistent with that previously demonstrated for the aromatic diisocyanate-based prepolymers.

Transduction of Single Nanomechanical Pillar Resonators by Scattering of Surface Acoustic Waves.

One of the challenges of nanoelectromechanical systems (NEMS) is the effective transduction of the tiny resonators. Vertical structures, such as nanomechanical pillar resonators, which are exploited in optomechanics, acoustic metamaterials, and nanomechanical sensing, are particularly challenging to transduce. Existing electromechanical transduction methods are ill-suited as they put constraints on the pillars' material and do not enable a transduction of freestanding pillars. Here, we present an electromechanical transduction method for single nanomechanical pillar resonators based on surface acoustic waves (SAWs). We demonstrate the transduction of freestanding nanomechanical platinum-carbon pillars in the first-order bending and compression mode. Since the principle of the transduction method is based on resonant scattering of a SAW by a nanomechanical resonator, our transduction method is independent of the pillar's material and not limited to pillar-shaped geometries. It represents a general method to transduce vertical mechanical resonators with nanoscale lateral dimensions.

Extracellular Microenvironment Alterations in Ductal Carcinoma In Situ and Invasive Breast Cancer Pathologies by Multiplexed Spatial Proteomics.

Ductal carcinoma in situ (DCIS) is a heterogeneous breast disease that remains challenging to treat due to its unpredictable progression to invasive breast cancer (IBC). Contemporary literature has become increasingly focused on extracellular matrix (ECM) alterations with breast cancer progression. However, the spatial regulation of the ECM proteome in DCIS has yet to be investigated in relation to IBC. We hypothesized that DCIS and IBC present distinct ECM proteomes that could discriminate between these pathologies. Tissue sections of pure DCIS, mixed DCIS-IBC, or pure IBC (n = 22) with detailed pathological annotations were investigated by multiplexed spatial proteomics. Across tissues, 1,005 ECM peptides were detected in pathologically annotated regions and their surrounding extracellular microenvironments. A comparison of DCIS to IBC pathologies demonstrated 43 significantly altered ECM peptides. Notably, eight fibrillar collagen peptides could distinguish with high specificity and sensitivity between DCIS and IBC. Lesion-targeted proteomic imaging revealed heterogeneity of the ECM proteome surrounding individual DCIS lesions. Multiplexed spatial proteomics reported an invasive cancer field effect, in which DCIS lesions in closer proximity to IBC shared a more similar ECM profile to IBC than distal counterparts. Defining the ECM proteomic microenvironment provides novel molecular insights relating to DCIS and IBC.

Trends in incidence of recorded diagnosis of osteoporosis, osteopenia, and fragility fractures in people aged 50 years and above: retrospective cohort study using UK primary care data.

This study used primary care data to estimate the incidence of recorded diagnosis of osteoporosis, osteopenia, and fragility fracture in the UK during 2000-2018 accounting for age, sex, calendar year and social deprivation. More than 3 million people aged 50-99 years were included. We found that men living in the most deprived areas had a 45% higher risk of being diagnosed with osteoporosis and 50% higher risk of fragility fracture compared to men living in the least deprived areas. PURPOSE: a) To estimate the incidence trends of a recorded diagnosis of osteoporosis, osteopenia, and fragility fracture in the UK over time; b) to describe differences according to age, sex, and social deprivation. METHODS: This is a longitudinal population-based cohort study using routinely collected primary care data obtained via IQVIA Medical Research Database (IMRD). All patients aged 50-99 years registered with a practice participating in THIN (The Health Improvement Network) between 2000-2018 were included. The first recorded diagnosis of osteoporosis, osteopenia, or fragility fracture was used to estimate incidence rates (IR) per 10,000 person-years at risk. Poisson regression was used to provide Incidence Rate Ratios (IRR) adjusted by age, sex, social deprivation, calendar year, and practice effect. RESULTS: The year-specific adjusted IRR of recorded osteoporosis was highest in 2009 in women [IRR 1.44(95%CI 1.38-1.50)], whereas in men it was highest in 2013-2014 [IRR 1.94(95%CI 1.72-2.18)] compared to 2000. The year-specific adjusted IRR of fragility fracture was highest in 2012 in women [IRR 1.77(95%CI 1.69-1.85)], whereas in men it was highest in 2013 [IRR 1.64(95%CI 1.51-1.78)] compared to 2000. Men in the most deprived areas had a higher risk of being diagnosed with osteoporosis [IRR 1.45(95%CI 1.38-1.53)], osteopenia [IRR 1.17(95%CI 1.09-1.26)], and fragility fracture [IRR 1.50(95%CI 1.44-1.56)] compared to those living in the least deprived areas, but smaller differences were seen in women. CONCLUSION: Use of fracture risk assessment tools may enhance the detection of osteoporosis cases in primary care. Further research is needed on the effect of social deprivation on diagnosis of osteoporosis and fractures.

E-cigarettes to Augment Stop Smoking In-person Support and Treatment With Varenicline (E-ASSIST): A Pragmatic Randomized Controlled Trial.

AIM: To examine whether, in adults receiving behavioral support, offering e-cigarettes together with varenicline helps more people stop smoking cigarettes than varenicline alone. METHODS: A two-group, parallel arm, pragmatic randomized controlled trial was conducted in six English stop smoking services from 2019-2020. Adults enrolled onto a 12-week programme of in-person one-to-one behavioral smoking cessation support (N  =  92) were randomized to receive either (1) a nicotine e-cigarette starter kit alongside varenicline or (2) varenicline alone. The primary outcome was biochemically verified abstinence from cigarette smoking between weeks 9-to-12 post quit date, with those lost to follow-up considered not abstinent. The trial was stopped early due to COVID-19 restrictions and a varenicline recall (92/1266 participants used). RESULTS: Nine-to-12-week smoking abstinence rates were 47.9% (23/48) in the e-cigarette-varenicline group compared with 31.8% (14/44) in the varenicline-only group, a 51% increase in abstinence among those offered e-cigarettes; however, the confidence interval (CI) was wide, including the possibility of no difference (risk ratio [RR] = 1.51, 95% CI = 0.91-2.64). The e-cigarette-varenicline group had 43% lower hazards of relapse from continuous abstinence than the varenicline-only group (hazards ratio [HR] = 0.57, 95% CI =  0.34-0.96). Attendance for 12 weeks was higher in the e-cigarette-varenicline than varenicline-only group (54.2% vs. 36.4%; RR = 1.49, 95% CI = 0.95-2.47), but similar proportions of participants in both groups used varenicline daily for ≥8 weeks after quitting (22.9% versus 22.7%; RR = 1.01, 95% CI = 0.47-2.20). Estimates were too imprecise to determine how adverse events differed by group. CONCLUSION: Tentative evidence suggests that offering e-cigarettes alongside varenicline to people receiving behavioral support may be more effective for smoking cessation than varenicline alone. IMPLICATIONS: Offering e-cigarettes to people quitting smoking with varenicline may help them remain abstinent from cigarettes, but the evidence is tentative because our sample size was smaller than planned-caused by Coronavirus Disease 2019 (COVID-19) restrictions and a manufacturing recall. This meant our effect estimates were imprecise, and additional evidence is needed to confirm that providing e-cigarettes and varenicline together helps more people remain abstinent than varenicline alone.

Blood loss and transfusion risk in intramedullary nailing for subtrochanteric fractures.

BACKGROUND: The incidence of hip fractures and subtrochanteric fractures in particular is increasing, along with the globally expanding aging population. Intramedullary nailing remains the 'gold standard' of their treatment. Blood loss can be a result of the original trauma, but also secondary to the subsequent surgical insult, especially during the reaming of the intramedullary canal. OBJECTIVES: The aim of our study was to report on the blood loss and incidence of blood transfusion in patients presenting with a subtrochanteric fracture treated with intramedullary nailing. Most importantly, we aim to identify factors associated with the need for transfusion within the first 48 h post-operatively. METHODS: Following institutional board approval, 431 consecutive patients (131 males; age: 79.03 years old, SD 13.68 years) presenting in a Level 1 Trauma Centre with a subtrochanteric fracture treated with an intramedullary nail were retrospectively identified, over an 8-year period. Exclusion criteria included patients with high energy injuries, pathological fractures, primary operations at other institutions and patients lost to follow-up. To identify risk factors leading to increased risk of transfusion, we first compared patients requiring intra-operative transfusion or transfusion during the first 48 h post-operatively against those who did not require transfusion. This was then followed by multivariate regression analysis adjusted for confounding factors to identify the most important risk factors associated with need for transfusion within the first 48 h post-operatively. RESULTS: Incidence of blood transfusion was 6.0% pre-operatively, compared to 62.7% post-operatively. A total of 230 patients (52.3%) required either intra-operative transfusion or transfusion during the first 48 h following surgery. Patients having a transfusion within the first 48 h post-operatively had a higher incidence of escalation in their care (p = 0.050), LOS (p = 0.015), 30-day (p = 0.033) and one-year mortality (p = 0.004). Multivariate regression analysis adjusted for confounding factors identified that the most important association of a need for transfusion within the first 48 post-operative hours was a pre-operative Hb <100 g/L (OR 6.64); a nail/canal ratio <70% (OR 3.92), followed by need for open reduction (OR 2.66). Fracture involving the lesser trochanter was also implicated with an increased risk (OR 2.08). Additionally, pre-operative moderate/severe renal impairment (OR 4.56), as well as hypoalbuminaemia on admission (OR 2.10) were biochemical predictors of an increased risk of transfusion. Most importantly, the need for transfusion was associated with an increase in 30-day mortality (OR 12.07). CONCLUSION: Several patient, fracture and surgery related factors are implicated with an increased risk for transfusion within the first 48-h post-operatively. Early identification, and where possible correction of these factors can potentially reduce blood loss and risk of transfusion, along with all the associated sequelae and mortality risk. LEVEL OF EVIDENCE: III.

Associations with Non-Persistence with Intra-Vitreal Therapy for Neovascular Age-Related Macular Degeneration at 24 Months.

AIMS: The aim of the study was to investigate non-persistence with treatment for neovascular age-related macular degeneration (NvAMD) before day 720 (24 months) after initiation, explore associations with baseline characteristics and variation between sites. METHODS: Anonymised demographic and clinical data were extracted from electronic medical records at treating National Health Service (NHS) Trusts for NvAMD eyes starting intra-vitreal therapy from 2017 to 2018. Time to non-persistence with treatment, defined as no recorded attendance for either monitoring or treatment for a period ≥6 months, was visualised with a Kaplan-Meier survival plot. Associations with treatment non-persistence were investigated using a Cox proportional hazards model. RESULTS: Analysis included 7,970 eyes of 7,112 patients treated at 13 NHS trusts. Censoring deaths and those eyes in which treatment was stopped permanently, the Kaplan-Meier analyses demonstrated survival figures of 77.7% for persistence with treatment to day 360 and 71.8% to day 720. Hazard ratios for non-persistence with treatment were reduced at 10 sites, relative to the reference, with first-treated eye status and with baseline acuity worse than or equal to LogMAR 1.0. Hazard ratios increased with younger age, in the presence of other ocular co-morbidities and with baseline acuity better than or equal to LogMAR 0.5. After an episode of non-persistence, visual acuity decreased by at least 0.1 and 0.3 LogMAR in 39% and 18% of eyes, respectively. CONCLUSIONS: Non-persistence with treatment was common, especially in the first year of treatment, and was often associated with a decrease in visual acuity. Treatment site, baseline visual acuity, and age were the strongest predictors of treatment non-persistence before day 720. Understanding and addressing reasons for non-persistence are important to ensure that effective but expensive treatments are used cost-effectively and to maintain acuity. Variation in non-persistence between sites, even after adjustment for other variables, suggests that local factors in treatment provision may be particularly important.