Hit it hard: qualitative patient perspectives on the optimisation of immune checkpoint inhibition.

BACKGROUND: Immune checkpoint inhibitors have transformed the treatment landscape of many cancers, including melanoma and renal cell carcinoma (RCC). Randomised trials are evaluating outcomes from reduced ICI treatment schedules with the aim of improving quality of life, tolerability, and cost-effectiveness. This study aims to provide insight into patient and carer's perspectives of these trials. METHODS: Seven focus groups were conducted with 31 people with stage IV melanoma, RCC, or caregivers for people receiving ICI. Transcripts were analysed using reflexive thematic analysis. RESULTS: Three themes were generated: 1) "Treatment and clinic visits provide reassurance": reducing hospital visits may not improve quality of life. 2) "Assessment of personal risk versus benefit": the decision to participate in an ICI optimisation trial is influenced by treatment response, experience of toxicity and perceived logistical benefits based on the individual's circumstances. 3) "Pre-existing experience and beliefs about how treatment and trials work", including the belief that more treatment is better, influence views around ICI optimisation trials. CONCLUSION: This study provides insight into recruitment challenges and recommends strategies to enhance recruitment for ongoing ICI optimisation trials. These findings will influence the design of future ICI optimisation trials ensuring they are acceptable to patients.

Measuring the effectiveness of online search ads on blood donor recruitment and donation.

BACKGROUND: Acutely highlighted during the COVID-19 pandemic, the tenuousness of the blood supply continues to be a lynchpin of the most important medical procedures. Online advertisements have become a mainstay in donor recruitment. We set out to determine the effectiveness of online search ads and variations thereof on blood donations with an emphasis on first-time donors. STUDY DESIGN AND METHODS: From September 01, 2022 through March 31, 2023, we performed a campaign comparison experiment through a major search-ads platform with two distinct messages: one altruistic ("Altruistic") and one with a prospect of rewards ("Promotion"). We developed a method to track donation outcomes and associated them with impressions, click-throughs, and conversions. We compared the performance of the Altruistic and Promotion arms to a control group that was not associated with any search-ads ("Baseline"). RESULTS: Analyzing 34,157 donations during the study period, the Promotion group, and not Altruistic, had a significant difference of first-time donors over Baseline (24% vs. 12%, p = 7e-6). We analyzed 49,305 appointments and discovered that appointments made from the Altruistic arm resulted in a significantly higher percentage of donations when compared to Baseline (57% vs. 53%, p = .009); however, the Promotion group had a higher percentage of donations from first-time donors when compared to Baseline (12% vs. 8%, p = .006). CONCLUSION: We developed a method for determining the effectiveness of online search ads on donation outcomes. Rewards/promotions messaging was most effective at recruiting first-time donors. Our methodology is generalizable to different blood centers to explore messaging effectiveness among their unique communities.

Evaluating accuracy and fairness of clinical decision support algorithms when health care resources are limited.

OBJECTIVE: Guidance on how to evaluate accuracy and algorithmic fairness across subgroups is missing for clinical models that flag patients for an intervention but when health care resources to administer that intervention are limited. We aimed to propose a framework of metrics that would fit this specific use case. METHODS: We evaluated the following metrics and applied them to a Veterans Health Administration clinical model that flags patients for intervention who are at risk of overdose or a suicidal event among outpatients who were prescribed opioids (N = 405,817): Receiver - Operating Characteristic and area under the curve, precision - recall curve, calibration - reliability curve, false positive rate, false negative rate, and false omission rate. In addition, we developed a new approach to visualize false positives and false negatives that we named 'per true positive bars.' We demonstrate the utility of these metrics to our use case for three cohorts of patients at the highest risk (top 0.5 %, 1.0 %, and 5.0 %) by evaluating algorithmic fairness across the following age groups: <=30, 31-50, 51-65, and >65 years old. RESULTS: Metrics that allowed us to assess group differences more clearly were the false positive rate, false negative rate, false omission rate, and the new 'per true positive bars'. Metrics with limited utility to our use case were the Receiver - Operating Characteristic and area under the curve, the calibration - reliability curve, and the precision - recall curve. CONCLUSION: There is no "one size fits all" approach to model performance monitoring and bias analysis. Our work informs future researchers and clinicians who seek to evaluate accuracy and fairness of predictive models that identify patients to intervene on in the context of limited health care resources. In terms of ease of interpretation and utility for our use case, the new 'per true positive bars' may be the most intuitive to a range of stakeholders and facilitates choosing a threshold that allows weighing false positives against false negatives, which is especially important when predicting severe adverse events.

Dura-based automated vault expansion remodelling (DAVE-R): automated planning of volume expansion in fronto-orbital advancement for trigonocephaly.

Cranial vault remodelling for craniosynostosis aims to increase intracranial volume to facilitate brain growth, avoid the development of raised intracranial pressure and address cosmesis. The extent of vault expansion is predominantly limited by scalp closure and reconstruction technique. Virtual surgical planning tools have been developed to predict post-operative changes and guide expansion. We present a validation study of a novel 'Dura-based Automated Vault Expansion-Remodeling' (DAVE-R) model to guide pre-operative planning for fronto-orbital advancement and remodelling (FOAR). METHODS: Patients with trigonocephaly who underwent FOAR with pre- and post-operative imaging from 2018 to 2020 were identified from a prospectively maintained database. Post-operative scans, normative atlas and whole brain parcellation were registered to the pre-operative images to quantify the change in intracranial volume and morphology (utilising measurement of fronto-orbital advancement and bifrontozygomatic distance) compared to that predicted by the DAVE-R model. RESULTS: Ten patients were included. The DAVE-R model predicted bifrontozygomatic distances of 92.0 + / - 5.14 mm (mean + /SD), which closely matched the post-operative results of 92.7 + / - 6.02 mm (mean + / - SD); (t(d.f. 9) = -0.306, p = 0.77). The fronto-orbital advancement predicted by the DAVE-R method was 11.5 + / - 1.96 mm (mean + / - SD) which was significantly greater than 8.6 + / - 2.94 mm (mean ± SD); (t(d.f. 9) = 3.137, p = 0.01) achieved post-operatively. CONCLUSIONS: We demonstrate that the DAVE-R model provides an objective means of extracting realistic surgical goals in patients undergoing FOAR for trigonocephaly that closely correlates with post-operative outcomes. The normative dural model warrants further study and validation for other forms of craniosynostosis correction.

The Multiplicative Effects of Individual Risk Factors in the Development of Osteonecrosis of the Femoral Head.

BACKGROUND: While individual risk factors, including chronic corticosteroid use, alcohol abuse, and smoking, are implicated in osteonecrosis of the femoral head (ONFH), the degree to which multiple risk factors increase risk is unknown. This study aimed to: (1) identify the demographic characteristics of patients who have ONFH; (2) quantify the effects of individual risk factors on ONFH development; (3) quantify the effects of combined risk factors on ONFH development; and (4) determine the prognostic implications of combined risk factors on ONFH development. METHODS: This was a retrospective cohort study. A national insurance database was used to study a population of 2,612,383 adult patients who had a 10-year follow-up period. There were 10,233 patients identified who had a diagnosis of ONFH. We identified patients who had chronic corticosteroid use, tobacco use, and/or alcohol abuse and assessed the risk of developing ONFH over a 10-year period. Patients who had individual and multiple risk factors were grouped for comparison, and Chi-square analyses were performed. RESULTS: Higher proportions of patients who had each individual risk factor developed ONFH compared to proportions of patients who did not have risk factors. Patients who had combined risk factors were at greater risk of developing ONFH compared to patients who had no risk factors and those who had single risk factors. Combined risk factors demonstrated multiplicative effects on the development of ONFH: tobacco-alcohol risk ratio (RR) 5.25, corticosteroid-alcohol RR 10.20, tobacco-corticosteroid RR 8.69, and corticosteroid-tobacco-alcohol RR 12.54. Patients who had combined risk factors developed ONFH at younger ages than those who had single risk factors. Kaplan-Meier curve analyses demonstrated worse 10-year hip survival in the setting of combined risk factors. CONCLUSIONS: Combined risk factors have a multiplicative effect on the risk of developing of atraumatic ONFH. Orthopaedic surgeons may care for at-risk individuals through modulation of risk factors. LEVEL OF EVIDENCE: Retrospective Cohort Study, Level III.

REFINE-Lung implements a novel multi-arm randomised trial design to address possible immunotherapy overtreatment.

Increasing evidence suggests that some immunotherapy dosing regimens for patients with advanced cancer could result in overtreatment. Given the high costs of these agents, and important implications for quality of life and toxicity, new approaches are needed to identify and reduce unnecessary treatment. Conventional two-arm non-inferiority designs are inefficient in this context because they require large numbers of patients to explore a single alternative to the standard of care. Here, we discuss the potential problem of overtreatment with anti-PD-1 directed agents in general and introduce REFINE-Lung (NCT05085028), a UK multicentre phase 3 study of reduced frequency pembrolizumab in advanced non-small-cell lung cancer. REFINE-Lung uses a novel multi-arm multi-stage response over continuous interventions (MAMS-ROCI) design to determine the optimal dose frequency of pembrolizumab. Along with a similarly designed basket study of patients with renal cancer and melanoma, REFINE-Lung and the MAMS-ROCI design could contribute to practice-changing advances in patient care and form a template for future immunotherapy optimisation studies across cancer types and indications. This new trial design is applicable to many new or existing agents for which optimisation of dose, frequency, or duration of therapy is desirable.

Cumulative burden of late, major surgical intervention in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study (CCSS) cohort.

BACKGROUND: Multimodal cancer therapy places childhood cancer survivors at increased risk for chronic health conditions, subsequent malignancies, and premature mortality as they age. We aimed to estimate the cumulative burden of late (>5 years from cancer diagnosis), major surgical interventions among childhood cancer survivors, compared with their siblings, and to examine associations between specific childhood cancer treatments and the burden of late surgical interventions. METHODS: We analysed data from the Childhood Cancer Survivor Study (CCSS), a retrospective cohort study with longitudinal prospective follow-up of 5-year survivors of childhood cancer (diagnosed before age 21 years) treated at 31 institutions in the USA, with a comparison group of nearest-age siblings of survivors selected by simple random sampling. The primary outcome was any self-reported late, major surgical intervention (defined as any anaesthesia-requiring operation) occurring 5 years or more after the primary cancer diagnosis. The cumulative burden was assessed with mean cumulative counts (MCC) of late, major surgical interventions. Piecewise exponential regression models with calculation of adjusted rate ratios (RRs) evaluated associations between treatment exposures and late, major surgical interventions. FINDINGS: Between Jan 1, 1970, and Dec 31, 1999, 25 656 survivors were diagnosed (13 721 male, 11 935 female; median follow-up 21·8 years [IQR 16·5-28·4]; median age at diagnosis 6·1 years [3·0-12·4]); 5045 nearest-age siblings were also included as a comparison group. Survivors underwent 28 202 late, major surgical interventions and siblings underwent 4110 late, major surgical interventions. The 35-year MCC of a late, major surgical intervention was 206·7 per 100 survivors (95% CI 202·7-210·8) and 128·9 per 100 siblings (123·0-134·7). The likelihood of a late, major surgical intervention was higher in survivors versus siblings (adjusted RR 1·8, 95% CI 1·7-1·9) and in female versus male survivors (1·4; 1·4-1·5). Survivors diagnosed in the 1990s (adjusted RR 1·4, 95% CI 1·3-1·5) had an increased likelihood of late surgery compared with those diagnosed in the 1970s. Survivors received late interventions more frequently than siblings in most anatomical regions or organ systems, including CNS (adjusted RR 16·9, 95% CI 9·4-30·4), endocrine (6·7, 5·2-8·7), cardiovascular (6·6, 5·2-8·3), respiratory (5·3, 3·4-8·2), spine (2·4, 1·8-3·2), breast (2·1, 1·7-2·6), renal or urinary (2·0, 1·5-2·6), musculoskeletal (1·5, 1·4-1·7), gastrointestinal (1·4, 1·3-1·6), and head and neck (1·2, 1·1-1·4) interventions. Survivors of Hodgkin lymphoma (35-year MCC 333·3 [95% CI 320·1-346·6] per 100 survivors), Ewing sarcoma (322·9 [294·5-351·3] per 100 survivors), and osteosarcoma (269·6 [250·1-289·2] per 100 survivors) had the highest cumulative burdens of late, major surgical interventions. Locoregional surgery or radiotherapy cancer treatment were associated with undergoing late surgical intervention in the same body region or organ system. INTERPRETATION: Childhood cancer survivors have a significant burden of late, major surgical interventions, a late effect that has previously been poorly quantified. Survivors would benefit from regular health-care evaluations aiming to anticipate impending surgical issues and to intervene early in the disease course when feasible. FUNDING: US National Institutes of Health, US National Cancer Institute, American Lebanese Syrian Associated Charities, and St Jude Children's Research Hospital.

Mutant Phosphodiesterase 3A Protects From Hypertension-Induced Cardiac Damage.

BACKGROUND: Phosphodiesterase 3A (PDE3A) gain-of-function mutations cause hypertension with brachydactyly (HTNB) and lead to stroke. Increased peripheral vascular resistance, rather than salt retention, is responsible. It is surprising that the few patients with HTNB examined so far did not develop cardiac hypertrophy or heart failure. We hypothesized that, in the heart, PDE3A mutations could be protective. METHODS: We studied new patients. CRISPR-Cas9-engineered rat HTNB models were phenotyped by telemetric blood pressure measurements, echocardiography, microcomputed tomography, RNA-sequencing, and single nuclei RNA-sequencing. Human induced pluripotent stem cells carrying PDE3A mutations were established, differentiated to cardiomyocytes, and analyzed by Ca2+ imaging. We used Förster resonance energy transfer and biochemical assays. RESULTS: We identified a new PDE3A mutation in a family with HTNB. It maps to exon 13 encoding the enzyme's catalytic domain. All hitherto identified HTNB PDE3A mutations cluster in exon 4 encoding a region N-terminally from the catalytic domain of the enzyme. The mutations were recapitulated in rat models. Both exon 4 and 13 mutations led to aberrant phosphorylation, hyperactivity, and increased PDE3A enzyme self-assembly. The left ventricles of our patients with HTNB and the rat models were normal despite preexisting hypertension. A catecholamine challenge elicited cardiac hypertrophy in HTNB rats only to the level of wild-type rats and improved the contractility of the mutant hearts, compared with wild-type rats. The ß-adrenergic system, phosphodiesterase activity, and cAMP levels in the mutant hearts resembled wild-type hearts, whereas phospholamban phosphorylation was decreased in the mutants. In our induced pluripotent stem cell cardiomyocyte models, the PDE3A mutations caused adaptive changes of Ca2+ cycling. RNA-sequencing and single nuclei RNA-sequencing identified differences in mRNA expression between wild-type and mutants, affecting, among others, metabolism and protein folding. CONCLUSIONS: Although in vascular smooth muscle, PDE3A mutations cause hypertension, they confer protection against hypertension-induced cardiac damage in hearts. Nonselective PDE3A inhibition is a final, short-term option in heart failure treatment to increase cardiac cAMP and improve contractility. Our data argue that mimicking the effect of PDE3A mutations in the heart rather than nonselective PDE3 inhibition is cardioprotective in the long term. Our findings could facilitate the search for new treatments to prevent hypertension-induced cardiac damage.

Thromboxane biosynthesis in cancer patients and its inhibition by aspirin: a sub-study of the Add-Aspirin trial.

BACKGROUND: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases. METHODS: Urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values. RESULTS: In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77-82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg. CONCLUSIONS: Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin.

Optogenetic Reporters Delivered as mRNA Facilitate Repeatable Action Potential and Calcium Handling Assessment in Human iPSC-Derived Cardiomyocytes.

Electrical activity and intracellular Ca2+ transients are key features of cardiomyocytes. They can be measured using organic voltage- and Ca2+-sensitive dyes but their photostability and phototoxicity mean they are unsuitable for long-term measurements. Here, we investigated whether genetically encoded voltage and Ca2+ indicators (GEVIs and GECIs) delivered as modified mRNA (modRNA) into human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) would be accurate alternatives allowing measurements over long periods. These indicators were detected in hiPSC-CMs for up to 7 days after transfection and did not affect responses to proarrhythmic compounds. Furthermore, using the GEVI ASAP2f we observed action potential prolongation in long QT syndrome models, while the GECI jRCaMP1b facilitated the repeated evaluation of Ca2+ handling responses for various tyrosine kinase inhibitors. This study demonstrated that modRNAs encoding optogenetic constructs report cardiac physiology in hiPSC-CMs without toxicity or the need for stable integration, illustrating their value as alternatives to organic dyes or other gene delivery methods for expressing transgenes.

A comparison of different population-level summary measures for randomised trials with time-to-event outcomes, with a focus on non-inferiority trials.

BACKGROUND: The population-level summary measure is a key component of the estimand for clinical trials with time-to-event outcomes. This is particularly the case for non-inferiority trials, because different summary measures imply different null hypotheses. Most trials are designed using the hazard ratio as summary measure, but recent studies suggested that the difference in restricted mean survival time might be more powerful, at least in certain situations. In a recent letter, we conjectured that differences between summary measures can be explained using the concept of the non-inferiority frontier and that for a fair simulation comparison of summary measures, the same analysis methods, making the same assumptions, should be used to estimate different summary measures. The aim of this article is to make such a comparison between three commonly used summary measures: hazard ratio, difference in restricted mean survival time and difference in survival at a fixed time point. In addition, we aim to investigate the impact of using an analysis method that assumes proportional hazards on the operating characteristics of a trial designed with any of the three summary measures. METHODS: We conduct a simulation study in the proportional hazards setting. We estimate difference in restricted mean survival time and difference in survival non-parametrically, without assuming proportional hazards. We also estimate all three measures parametrically, using flexible survival regression, under the proportional hazards assumption. RESULTS: Comparing the hazard ratio assuming proportional hazards with the other summary measures not assuming proportional hazards, relative performance varies substantially depending on the specific scenario. Fixing the summary measure, assuming proportional hazards always leads to substantial power gains compared to using non-parametric methods. Fixing the modelling approach to flexible parametric regression assuming proportional hazards, difference in restricted mean survival time is most often the most powerful summary measure among those considered. CONCLUSION: When the hazards are likely to be approximately proportional, reflecting this in the analysis can lead to large gains in power for difference in restricted mean survival time and difference in survival. The choice of summary measure for a non-inferiority trial with time-to-event outcomes should be made on clinical grounds; when any of the three summary measures discussed here is equally justifiable, difference in restricted mean survival time is most often associated with the most powerful test, on the condition that it is estimated under proportional hazards.

Ambient Air Pollutant Exposures and COVID-19 Severity and Mortality in a Cohort of Patients with COVID-19 in Southern California.

Rationale: Ecological studies have shown air pollution associations with coronavirus disease (COVID-19) outcomes. However, few cohort studies have been conducted. Objectives: To conduct a cohort study investigating the association between air pollution and COVID-19 severity using individual-level data from the electronic medical record. Methods: This cohort included all individuals who received diagnoses of COVID-19 from Kaiser Permanente Southern California between March 1 and August 31, 2020. One-year and 1-month averaged ambient air pollutant (particulate matter ⩽2.5 µm in aerodynamic diameter [PM2.5], NO2, and O3) exposures before COVID-19 diagnosis were estimated on the basis of residential address history. Outcomes included COVID-19-related hospitalizations, intensive respiratory support (IRS), and ICU admissions within 30 days and mortality within 60 days after COVID-19 diagnosis. Covariates included socioeconomic characteristics and comorbidities. Measurements and Main Results: Among 74,915 individuals (mean age, 42.5 years; 54% women; 66% Hispanic), rates of hospitalization, IRS, ICU admission, and mortality were 6.3%, 2.4%, 1.5%, and 1.5%, respectively. Using multipollutant models adjusted for covariates, 1-year PM2.5 and 1-month NO2 average exposures were associated with COVID-19 severity. The odds ratios associated with a 1-SD increase in 1-year PM2.5 (SD, 1.5 µg/m3) were 1.24 (95% confidence interval [CI], 1.16-1.32) for COVID-19-related hospitalization, 1.33 (95% CI, 1.20-1.47) for IRS, and 1.32 (95% CI, 1.16-1.51) for ICU admission; the corresponding odds ratios associated with 1-month NO2 (SD, 3.3 ppb) were 1.12 (95% CI, 1.06-1.17) for hospitalization, 1.18 (95% CI, 1.10-1.27) for IRS, and 1.21 (95% CI, 1.11-1.33) for ICU admission. The hazard ratios for mortality were 1.14 (95% CI, 1.02-1.27) for 1-year PM2.5 and 1.07 (95% CI, 0.98-1.16) for 1-month NO2. No significant interactions with age, sex or ethnicity were observed. Conclusions: Ambient PM2.5 and NO2 exposures may affect COVID-19 severity and mortality.

What Are the Functional and Surgical Outcomes of Tibial Turnup-plasty for Salvage in Patients With Chronic Lower Extremity Infection?

BACKGROUND: Tibial turnup-plasty is a rarely performed surgical option for large bone defects of the distal or entire femur and can serve as an alternative to hip disarticulation or high above-knee amputation. It entails pedicled transport of the ipsilateral tibia with or without the proximal hindfoot for use as a vascularized autograft. It is rotated 180° in the coronal or sagittal plane to the remaining proximal femur or pelvis, augmenting the functional length of the thigh. Prior reports consist of small case series with heterogeneous surgical techniques. Patient-reported outcome measures after the procedure have not been reported, and ambulatory status after the procedure is also unknown. QUESTIONS/PURPOSES: (1) What proportion of patients underwent reoperation after tibial turnup-plasty? (2) What is the ambulatory status and what proportion of patients used a prosthesis after tibial turnup-plasty? (3) What are the Patient-Reported Outcome Measurement Information System (PROMIS) Global-10 mental and physical function scores after tibial turnup-plasty? METHODS: A retrospective analysis was performed of 11 patients who underwent tibial turnup-plasty between 2003 and 2021 by a single orthopaedic oncology division in collaboration with a reconstructive plastic surgery team. Nine patients were men, with a median age of 55 years (range 34 to 75 years). All had chronic infections after arthroplasty or oncologic reconstructions, with a median number of 13 surgeries before turnup-plasty. All were considered to have no other surgical options other than hip disarticulation or high transfemoral amputation. All patients who were offered this possibility accepted it. Data of interest included patient demographics and comorbidities, surgical history that led to limb compromise, medical and surgical perioperative complications, date of prosthesis fitting, and functional capacity at the most recent follow-up interval based on ambulatory status and PROMIS Global-10 mental and physical function scores. The statistical analysis was descriptive. RESULTS: The median number of reoperations after turnup-plasty was one (range 0 to 11). Of the six patients who underwent at least one reoperation, indications for surgery included wound infection (four patients), nonunion of the osteosynthesis site (two), heterotopic ossification (one), tumor recurrence (one), and flap hypoperfusion treated with local tissue revision (one). One patient underwent conversion to external hemipelvectomy for tumor recurrence. Ten of the 11 patients were ambulatory at the final follow-up interval with standard above-knee amputation prostheses. Two ambulated unassisted, four used a single crutch or cane, and four used two crutches or a walker. Of the nine patients for whom scores were available, the median PROMIS Global-10 physical and mental health scores were 48 (range 30 to 68) and 53 (range 41 to 68), both within the standard deviation of the population mean of 50. CONCLUSION: The tibial turnup-plasty is a complex surgical option for patients with large bone defects of the femur for whom there are no alternative surgeries capable of producing residual extremities with acceptable functional length. This should be viewed as a procedure of last resort to avoid a hip disarticulation or a high transfemoral amputation in patients who have typically undergone numerous prior operations. Although ambulation with a prosthesis within 1 year can be expected, almost all patients will require an assistive device to do so, and reoperations are frequent. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial.

BACKGROUND: STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL). METHODS AND FINDINGS: Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire. Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79, p < 0.001; 375 SOC versus 386 SOC+RT, HR = 1.11, 95% CI 0.96, 1.28, p = 0·164; interaction p < 0.001). No evidence of difference in time to symptomatic local events was found. There was no evidence of difference in Global QoL or QLQ-30 Summary Score. Long-term urinary toxicity of grade 3 or worse was reported for 10 SOC and 10 SOC+RT; long-term bowel toxicity of grade 3 or worse was reported for 15 and 11, respectively. CONCLUSIONS: Prostate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC. TRIAL REGISTRATION: ClinicalTrials.gov NCT00268476, ISRCTN.com ISRCTN78818544.

Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme.

BACKGROUND: Androgen suppression is a central component of prostate cancer management but causes substantial long-term toxicity. Transdermal administration of oestradiol (tE2) circumvents first-pass hepatic metabolism and, therefore, should avoid the cardiovascular toxicity seen with oral oestrogen and the oestrogen-depletion effects seen with luteinising hormone releasing hormone agonists (LHRHa). We present long-term cardiovascular follow-up data from the Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme. METHODS: PATCH is a seamless phase 2/3, randomised, multicentre trial programme at 52 study sites in the UK. Men with locally advanced or metastatic prostate cancer were randomly allocated (1:2 from August, 2007 then 1:1 from February, 2011) to either LHRHa according to local practice or tE2 patches (four 100 µg patches per 24 h, changed twice weekly, reducing to three patches twice weekly if castrate at 4 weeks [defined as testosterone ≤1·7 nmol/L]). Randomisation was done using a computer-based minimisation algorithm and was stratified by several factors, including disease stage, age, smoking status, and family history of cardiac disease. The primary outcome of this analysis was cardiovascular morbidity and mortality. Cardiovascular events, including heart failure, acute coronary syndrome, thromboembolic stroke, and other thromboembolic events, were confirmed using predefined criteria and source data. Sudden or unexpected deaths were attributed to a cardiovascular category if a confirmatory post-mortem report was available and as other relevant events if no post-mortem report was available. PATCH is registered with the ISRCTN registry, ISRCTN70406718; the study is ongoing and adaptive. FINDINGS: Between Aug 14, 2007, and July 30, 2019, 1694 men were randomly allocated either LHRHa (n=790) or tE2 patches (n=904). Overall, median follow-up was 3·9 (IQR 2·4-7·0) years. Respective castration rates at 1 month and 3 months were 65% and 93% among patients assigned LHRHa and 83% and 93% among those allocated tE2. 157 events from 145 men met predefined cardiovascular criteria, with a further ten sudden deaths with no post-mortem report (total 167 events in 153 men). 26 (2%) of 1694 patients had fatal cardiovascular events, 15 (2%) of 790 assigned LHRHa and 11 (1%) of 904 allocated tE2. The time to first cardiovascular event did not differ between treatments (hazard ratio 1·11, 95% CI 0·80-1·53; p=0·54 [including sudden deaths without post-mortem report]; 1·20, 0·86-1·68; p=0·29 [confirmed group only]). 30 (34%) of 89 cardiovascular events in patients assigned tE2 occurred more than 3 months after tE2 was stopped or changed to LHRHa. The most frequent adverse events were gynaecomastia (all grades), with 279 (38%) events in 730 patients who received LHRHa versus 690 (86%) in 807 patients who received tE2 (p<0·0001) and hot flushes (all grades) in 628 (86%) of those who received LHRHa versus 280 (35%) who received tE2 (p<0·0001). INTERPRETATION: Long-term data comparing tE2 patches with LHRHa show no evidence of a difference between treatments in cardiovascular mortality or morbidity. Oestrogens administered transdermally should be reconsidered for androgen suppression in the management of prostate cancer. FUNDING: Cancer Research UK, and Medical Research Council Clinical Trials Unit at University College London.

Assessing the Safety and Utility of Wound VAC Temporization of the Sarcoma or Benign Aggressive Tumor Bed Until Final Margins Are Achieved.

BACKGROUND: Local recurrence of microinvasive sarcoma or benign aggressive pathologies can be limb- and life-threatening. Although frozen pathology is reliable, tumor microinvasion can be subtle or missed, having an impact on surgical margins and postoperative radiation planning. The authors' service has begun to temporize the tumor bed after primary tumor excision with a wound vacuum-assisted closure (VAC) pending formal margin analysis, with coverage performed in the setting of final negative margins. METHODS: This retrospective analysis included all patients managed at a tertiary referral cancer center with VAC temporization after soft tissue sarcoma or benign aggressive tumor excision from 1 January 2000 to 1 January 2019 and at least 2 years of oncologic follow-up evaluation. The primary outcome was local recurrence. The secondary outcomes were distant recurrence, unplanned return to the operating room for wound/infectious indications, thromboembolic events, and tumor-related deaths. RESULTS: For 62 patients, VAC temporization was performed. The mean age of the patients was 62.2 ± 22.3 years (median 66.5 years; 95% confidence interval [CI] 61.7-72.5 years), and the mean age-adjusted Charlson Comorbidity Index was 5.3 ± 1.9. The most common tumor histology was myxofibrosarcoma (51.6%, 32/62). The mean volume was 124.8 ± 324.1 cm3, and 35.5% (22/62) of the cases were subfascial. Local recurrences occurred for 8.1% (5/62) of the patients. Three of these five patients had planned positive margins, and 17.7% (11/62) of the patients had an unplanned return to the operating room. No demographic or tumor factors were associated with unplanned surgery. CONCLUSIONS: The findings showed that VAC-temporized management of microinvasive sarcoma and benign aggressive pathologies yields favorable local recurrence and unplanned operating room rates suggestive of oncologic and technical safety. These findings will need validation in a future randomized controlled trial.

The role of the colonic microbiota and bile acids in colorectal cancer.

PURPOSE OF REVIEW: Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer-related deaths. Of the various established risk factors for this aggressive condition, diet is a notable modifiable risk factor. This review aims to summarize the mounting evidence to suggest the role of diet, the microbiota and their cross-talk in modulating an individual's risk of developing CRC. RECENT FINDINGS: Specifically, the metabolism of bile acids and its symbiosis with the microbiota has gained weight given its basis on a high meat, high fat, and low fibre diet that is present in populations with the highest risk of CRC. Bacteria modify bile acids that escape enterohepatic circulation to increase the diversity of the human bile acid pool. The production of microbial bile acids contributes to this as well. Epidemiological studies have shown that changing the diet results in different levels and composition of bile acids, which has in turn modified the risk of CRC at a population level. Evidence to identify underlying mechanisms have tied into the microbiota-led digestions of various foods into fatty acids that feedback into bile acid physiology as well as modulation of endogenous receptors for bile acids. SUMMARY: There is adequate evidence to support the role of microbiota in in the metabolism of bile acids, and how this relates to colorectal cancer. Further work is necessary to identify specific bacteriome involved and their underlying mechanistic pathways.

Bayesian parameter estimation for automatic annotation of gene functions using observational data and phylogenetic trees.

Gene function annotation is important for a variety of downstream analyses of genetic data. But experimental characterization of function remains costly and slow, making computational prediction an important endeavor. Phylogenetic approaches to prediction have been developed, but implementation of a practical Bayesian framework for parameter estimation remains an outstanding challenge. We have developed a computationally efficient model of evolution of gene annotations using phylogenies based on a Bayesian framework using Markov Chain Monte Carlo for parameter estimation. Unlike previous approaches, our method is able to estimate parameters over many different phylogenetic trees and functions. The resulting parameters agree with biological intuition, such as the increased probability of function change following gene duplication. The method performs well on leave-one-out cross-validation, and we further validated some of the predictions in the experimental scientific literature.

Modeling the longitudinal transitions of electronic cigarettes and conventional cigarettes with time-dependent covariates among adolescents.

E-cigarettes may help combustible cigarette smokers switch to a less harmful alternative, or may increase the risk of subsequent initiation of cigarettes among non-smokers. Among youth, it is not clear whether both pathways occur equally, or whether one direction is more likely than the other. We used data from a prospective cohort study of youth in Southern California followed twice annually from Fall 2013 (9th grade) to Fall 2015 (11th grade) (N = 1977). A polytomous logistic regression model was used to simultaneously estimate transition rates for initiation of and abstention from e-cigarettes and cigarettes. Use of e-cigarettes was positively associated with initiation of cigarettes (OR = 7.57; 95%CI:[5.32, 10.8]) and negatively associated with cigarette abstention (OR = 0.58; 95%CI:[0.33, 0.99]) in adjusted models; cigarette use was positively associated with e-cigarette initiation (OR = 2.54; 95%CI:[1.45, 4.47]) and negatively associated with e-cigarette abstention (OR = 0.31; 95%CI:[0.17,0.57]). Uni-directional transition from e-cigarettes only to cigarettes only occurred less frequently than expected under independence (OR = 0.33; 95% CI [0.20, 0.55]), whereas simultaneously initiating both products (OR = 9.79; 95%CI:[7.22, 13.3]) and simultaneously abstaining (OR = 2.84; 95%CI:[1.50, 5.37]) were more frequent than expected. E-cigarettes were more strongly associated with subsequent cigarette initiation than the reverse, though both models indicated that use of either product seems to encourage use of the other. Models also indicated that use of either e-cigarettes or cigarettes resulted in reduced abstention of the other product. Findings suggest that prevention efforts for that continue to focus on both e-cigarettes and cigarettes are needed.

Ambient air pollution and COVID-19 incidence during four 2020-2021 case surges.

BACKGROUND: Air pollution exposure may make people more vulnerable to COVID-19 infection. However, previous studies in this area mostly focused on infection before May 2020 and long-term exposure. OBJECTIVE: To assess both long-term and short-term exposure to air pollution and COVID-19 incidence across four case surges from 03/1/2020 to 02/28/2021. METHODS: The cohort included 4.6 million members from a large integrated health care system in southern California with comprehensive electronic medical records (EMR). COVID-19 cases were identified from EMR. Incidence of COVID-19 was computed at the census tract-level among members. Prior 1-month and 1-year averaged air pollutant levels (PM2.5, NO2, and O3) at the census tract-level were estimated based on hourly and daily air quality data. Data analyses were conducted by each wave: 3/1/2020-5/31/2020, 6/1/202-9/30/2020, 10/1/2020-12/31/2020, and 1/1/2021-2/28/2021 and pooled across waves using meta-analysis. Generalized linear mixed effects models with Poisson distribution and spatial autocorrelation were used with adjustment for meteorological factors and census tract-level social and health characteristics. Results were expressed as relative risk (RR) per 1 standard deviation. RESULTS: The cohort included 446,440 COVID-19 cases covering 4609 census tracts. The pooled RRs (95% CI) of COVID-19 incidence associated with 1-year exposures to PM2.5, NO2, and O3 were 1.11 (1.04, 1.18) per 2.3 µg/m3,1.09 (1.02, 1.17) per 3.2 ppb, and 1.06 (1.00, 1.12) per 5.5 ppb respectively. The corresponding RRs (95% CI) associated with prior 1-month exposures were 1.11 (1.03, 1.20) per 5.2 µg/m3 for PM2.5, 1.09 (1.01, 1.17) per 6.0 ppb for NO2 and 0.96 (0.85, 1.08) per 12.0 ppb for O3. CONCLUSION: Long-term PM2.5 and NO2 exposures were associated with increased risk of COVID-19 incidence across all case surges before February 2021. Short-term PM2.5 and NO2 exposures were also associated. Our findings suggest that air pollution may play a role in increasing the risk of COVID-19 infection.