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Background Process evaluation within clinical trials provides an assessment of the study implementation's accuracy and quality to explain causal mechanisms and highlight contextual factors associated with variation in outcomes. Objectives This study aimed to identify the barriers and facilitators of implementing early mobilisation (EM) within a trial. Methods This is a qualitative process evaluation study within the Trial of Early Activity and Mobilisation (TEAM) phase 3 randomised controlled trial. Semistructured interviews were conducted remotely with multiprofessional clinicians (physiotherapists, medical staff, and nursing staff) involved in the delivery of the TEAM intervention at Australian hospitals participating in the TEAM study. Inductive coding was used to establish themes which were categorised into the Behaviour system involving domains of Capability, Opportunity, and Motivation (COM-B), which allowed barriers and enablers affecting EM to be identified. Findings Semistructured interviews were conducted in three different states of Australia. There were 16 participants, including 10 physiotherapists, five physicians, and one nurse. The key themes that facilitated EM were mentoring, champions, additional staff, organisation of the environment, cultural changes, communication, and documented safety criteria. In contrast, the main factors that hindered EM were lack of expertise and confidence in delivering EM, heavy sedation, interdisciplinary conflicts, and perceived risks related to EM. Conclusion A wide range of barriers and facilitators that influenced EM within the TEAM study were identified using the COM-B framework. Many of these have been previously identified in the literature; however, participation in the study was viewed positively by multidisciplinary team members.

The results of sediment-stratigraphic, diatom and pollen analyses, and AMS 14C dating of salt marsh sediments at Higgin’s Neuk, Airth in the inner Forth estuary in central Scotland are reported. En...

OBJECTIVE: To describe the protocol and statistical analysis plan for the Treatment of Invasively Ventilated Adults with Early Activity and Mobilisation (TEAM III) trial. DESIGN: An international, multicentre, parallel-group, randomised controlled phase 3 trial. SETTING: Intensive care units (ICUs) in Australia, New Zealand, Germany, Ireland, the United Kingdom and Brazil. PATIENTS: 750 adult patients expected to receive mechanical ventilation for more than 48 hours. INTERVENTIONS: Early activity and mobilisation delivered to critically ill patients in an ICU for up to 28 days compared with standard care. MAIN OUTCOME MEASURES: The primary outcome is the number of days alive and out of hospital at 180 days after randomisation. Secondary outcomes include ICU-free days, ventilator-free days, delirium-free days, all-cause mortality at 28 and 180 days after randomisation, and functional outcome at 180 days after randomisation. RESULTS: Recruitment at 46 research sites passed 576 patients in March 2021. Final collection of all 180-day outcome data for the target of 750 patients is anticipated by May 2022. CONCLUSIONS: Consistent with international guidelines, a detailed protocol and prospective analysis plan has been developed for the TEAM III trial. This plan specifies the statistical models for evaluating primary and secondary outcomes, defines covariates for adjusted analyses, and defines methods for exploratory analyses. Application of this protocol and statistical analysis plan to the forthcoming TEAM III trial will facilitate unbiased analyses of the clinical data collected. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03133377.

Neoadjuvant systemic therapy has many potential advantages over up-front surgery, including tumor downstaging, early treatment of micrometastatic disease, and providing an in vivo test of tumor biology. Due to these advantages, neoadjuvant therapy is becoming the standard of care for an increasing number of tumor types. Currently, colon cancer patients are still routinely treated with up-front surgery, and neoadjuvant systemic therapy is not yet standard. Limitations to widespread use of neoadjuvant therapy have included inaccurate radiological staging, concerns about tumor progression while undergoing preoperative treatment rendering a patient incurable, and a lack of randomized data demonstrating benefit. However, there is great interest in neoadjuvant chemotherapy, and a number of trials are under way. Early follow up of the first phase III trial of neoadjuvant chemotherapy for colon cancer demonstrated tumor downstaging and suggested an improvement in disease-free survival with neoadjuvant chemotherapy, and it is hoped that this will translate into longer-term overall survival benefit. Clinicians should closely watch this developing field, consider the option of neoadjuvant chemotherapy for colon cancer patients, and actively seek out opportunities for their patients to participate in ongoing clinical trials to further inform this field in future.

Introduction: Colorectal cancer (CRC) is the third most common malignancy worldwide, with recent trends demonstrating increasing incidence amongst younger patients. Despite multiple treatment options, metastatic disease remains incurable. A new therapeutic strategy to harness the host immune system, specifically with immune checkpoint inhibitors, now has reported results from a number of clinical trials. Areas covered: This review will discuss in detail microsatellite instability (MSI) and other biomarkers for response to immunotherapy, summarize the pivotal clinical trials of immune checkpoint inhibitors in early-stage and metastatic MSI colorectal cancer, explore strategies to induce treatment responses in MSS CRC and highlight the emerging treatments and novel immune-based therapies under investigation. Expert opinion: Immunotherapy is now a standard of care for the proportion of CRC patients with MSI. While overall survival data are still awaited, the promise of profound and durable responses is highly anticipated. The lack of efficacy in MSS CRC is disappointing and strategies to convert these 'cold' tumors are needed. Further elucidation of optimal use of treatment sequences, combinations and novel agents will improve outcomes.

Background Imipenem combined with the β-lactamase inhibitor relebactam has broad antibacterial activity, including against carbapenem-resistant gram-negative pathogens. We evaluated efficacy and safety of imipenem/cilastatin/relebactam in treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP). Methods This was a randomized, controlled, double-blind phase 3 trial. Adults with HABP/VABP were randomized 1:1 to imipenem/cilastatin/relebactam 500 mg/500 mg/250 mg or piperacillin/tazobactam 4 g/500 mg, intravenously every 6 hours for 7–14 days. The primary endpoint was day 28 all-cause mortality in the modified intent-to-treat (MITT) population (patients who received study therapy, excluding those with only gram-positive cocci at baseline). The key secondary endpoint was clinical response 7–14 days after completing therapy in the MITT population. Results Of 537 randomized patients (from 113 hospitals in 27 countries), the MITT population comprised 264 imipenem/cilastatin/relebactam and 267 piperacillin/tazobactam patients; 48.6% had ventilated HABP/VABP, 47.5% APACHE II score ≥15, 24.7% moderate/severe renal impairment, 42.9% were ≥65 years old, and 66.1% were in the intensive care unit. The most common baseline pathogens were Klebsiella pneumoniae (25.6%) and Pseudomonas aeruginosa (18.9%). Imipenem/cilastatin/relebactam was noninferior (P, Imipenem/cilastatin/relebactam was noninferior to piperacillin/tazobactam for treating hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP), with a comparable tolerability profile. Imipenem/cilastatin/relebactam is an efficacious treatment option for nosocomial pneumonia, including HABP/VABP in mechanically ventilated and critically ill, high-risk patients.

Despite advances, patients with metastatic colorectal cancer (mCRC) still have poor long-term survival. Identification of molecular subtypes is important to guide therapy through standard treatment pathways and holds promise for the development of new treatments. Following standard first- and second-line chemotherapy plus targeted agents, many patients retain a reasonable performance status, and thus are seeking further effective treatment to extend life and maintain symptom control. The challenge lies in selecting the most appropriate therapy in the third- and fourth-line settings, from a range of options including the relatively new oral agents TAS-102 and regorafenib, or rechallenge with previous chemotherapy or anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies (mAB). Beyond this, therapy consists of trials involving novel agents and new combinations of treatments with theoretical synergy and/or non-overlapping toxicity. There is a great focus on enhancing immunogenicity in mCRC, to reflect the impressive results of immunotherapy drugs in the small cohort with mismatch repair deficient (dMMR) mCRC. Rare molecular subtypes of mCRC are increasingly being identified, including Her2-positive disease, NTRK fusions and others. Clinical trials exploring the efficacy of immunomodulatory and precision agents are plentiful and will hopefully yield clinically meaningful results that can be rapidly translated into routine care.

Background As our population ages, older adults are increasingly exposed to trauma. Frailty could be a useful measure to identify patients at risk of a poor outcome. This study aimed to determine the impact of frailty in an Australian trauma intensive care unit (ICU) population. Methods A prospective observational study of critically ill trauma patients ≥50 years of age. Frailty was determined on admission to the ICU using the frailty phenotype. Demographic and hospital data were collected, and patients were followed up at 6 and 12 months. The primary outcome was 12-month mortality, and multiple regression was used to determine associated factors. Results One hundred thirty-eight patients were included, whose mean age was 68 years; 78.2% (108/138) were classified as major trauma (Injury Severity Score >12). Twenty-two percent (30/138) of patients were identified as frail. Patients with frailty were significantly older: however, they were less severely injured and required lower rates of surgical interventions and mechanical ventilation. Frailty was independently associated with mortality at 6 and 12 months (odds ratio: 5.9, 95% confidence interval: 1.9–18.1 and odds ratio: 7.3, 95% confidence interval: 2.5–21.9, respectively). Patients with frailty had lower measures of global functioning (Glasgow Outcome Scale-Extended frail 3 [1–5] vs nonfrail 6 [(5–7], p = 0.002) and health status (Euro Qol 5Q-5D-5L utility score 0.6 [0.5–0.7] vs 0.7 [0.6–0.9], p = 0.02) at 12 months than patients without frailty. Conclusion Frailty is a useful predictor of poor outcomes in critically ill trauma patients. Registration of protocol number ACTRN12615000039583.

ObjectivePatients in the last year of life experience medical emergencies which may lead to an emergency attendance by ambulance clinicians and some patients having a transfer to hospital even when this is unwanted by patients, carers or professionals. Here we report the patient characteristics and outcomes of a 24-hour hospice nursing telephone advice service to support an ambulance service.MethodAn evaluation of the outcomes of ambulance calls to a nursing telephone advice service for people living in northwest London, UK, attended at home during a 6-month period by the London Ambulance Service, whose clinicians then sought advice from the hospice’s 24 hours’ telephone line.ResultsForty-five attendances of 44 acutely ill people with palliative care needs resulted in a telephone call. Thirteen patients (30%) were male and the median age was over 80 years. Thirty-two attendances (71%) were managed without a transfer to hospital, with telephone advice from the hospice and in some cases arrangements for another clinician to visit. Seven attendances (16%) resulted in a transfer to hospital, of which at least five led to an admission. Six attendances (13%) resulted in a notification of the patient’s death.ConclusionsThis preliminary study shows the feasibility, outcomes and acceptability of telephone advice to support ambulance clinicians attending patients with palliative care needs. The service was associated with low rates of subsequent transfer to hospital. Further controlled research is needed to assess the clinical and cost-effectiveness of the service.

Bacterial vaginosis (BV) is the most common gynecologic infection in women aged 14 to 49 years. Currently recommended treatments require extended dosing and are thus associated with poor adherence. A single-dose oral granule formulation of secnidazole 2 g (SOLOSEC™ [secnidazole], Symbiomix Therapeutics, a Lupin company, Baltimore, MD), a 5-nitroimidazole antibiotic with antimicrobial activity, has been approved by the US Food and Drug Administration for the treatment of BV in adult women. As part of the US registration package, two randomized, double-blind, placebo-controlled clinical studies were conducted to confirm the efficacy and safety of a novel single-dose oral formulation of secnidazole 2 g. This is an integrated analysis of efficacy and safety results from these studies, pivotal study 1 and pivotal study 2. By combining the results of the two studies, relevant information is presented especially when considering the effect of secnidazole on patients with recurrent episodes of BV and the difference in effect on patients of black race. Single-dose secnidazole 2 g was statistically superior to placebo on all primary and secondary efficacy outcomes in both trials, including clinical outcome responder rate (P P P P

Publisher's version (útgefin grein), Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied. Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms. Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need., The work of the co-ordinating centre was funded by the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/ 002), British Heart Foundation Cambridge Cardiovascular Centre of Excellence, UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (268834), and European Commission Framework Programme 7 (HEALTH-F2-2012-279233). The Emerging Risk Factor Collaboration’s website https://www.phpc.cam.ac.uk/ceu/erfc/list-of-studies/ has compiled a list provided by investigators of some of the funders of the component studies in this analysis. I.W. was supported by the Medical Research Council Unit Programme MC_UU_12023/21. M.K. is supported by the Netherlands Organization for Scientific Research (NWO) Veni grant (Veni, 91616079). J.P. is supported by Erasmus Mundus Western Balkans (ERAWEB), a project funded by the European Commission.

The Internal Dosimetry User Group (IDUG) is an independent, non-profit group of medical professionals dedicated to the promotion of dosimetry in molecular radiotherapy ( www.IDUG.org.uk ). The Ionising Radiation (Medical Exposure) Regulations 2017, IR(ME)R, stipulate a requirement for optimisation and verification of molecular radiotherapy treatments, ensuring doses to non-target organs are as low as reasonably practicable. For many molecular radiotherapy treatments currently undertaken within the UK, this requirement is not being fully met. The growth of this field is such that we risk digressing further from IR(ME)R compliance potentially delivering suboptimal therapies that are not in the best interest of our patients. For this purpose, IDUG proposes ten points of action to aid in the successful implementation of this legislation. We urge stakeholders to support these proposals and ensure national provision is sufficient to meet the criteria necessary for compliance, and for the future advancement of molecular radiotherapy within the UK.

PurposeImproving valuation accuracy, especially for sale and acquisition purposes, remains one of the key targets of the global real estate research agenda. Among other recommendations, it has been argued that the use of technology-based advanced valuation methods can help to narrow the gap between asset valuations and actual sale prices. The purpose of this paper is to investigate the property valuation methods being adopted by Australian valuers and the factors influencing their level of awareness and adoption of the methods.Design/methodology/approachAn online questionnaire survey was conducted to elicit information from valuers practising in Australia. They were asked to indicate their level of awareness and adoption of the different property valuation methods. Their response was analysed using frequency distribution,χ2test and mean score ranking.FindingsThe results show that the traditional methods of valuation, namely, comparative, investment and residual, are the most adopted methods by the Australian valuers, while advanced valuation methods are seldom applied in practice. The results confirm that professional bodies, sector of practice and educational institutions are the three most important drivers of awareness and adoption of the advanced valuation methods.Practical implicationsThere is a need for all the property valuation stakeholders to synergise and transform the property valuation practice in a bid to promote the awareness and adoption of advanced valuation methods, (e.g. hedonic pricing model, artificial neural network, expert system, fuzzy logic system, etc.) among valuers. These are all technology-based methods to improve the efficiency in the prediction process, and the valuer still needs to input reliable transaction data into the systems.Originality/valueThis study provides a fresh and most recent insight into the current property valuation methods adopted in practice by valuers practising in Australia. It identifies that the advanced valuation methods could supplement the traditional valuation methods to achieve good practice standard for improving the professional valuation practice in Australia so that the valuation profession can meet the industry’s expectations.

Background Gene-modified autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells. Methods Four cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay. Results Responses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163+ tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5%) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients. Conclusions Our studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy. Trial registration ClinicalTrials.gov, NCT01343043, Registered 27 April 2011.

Background There is variability in access to and utilization of orthopaedic care, particularly for those with Medicaid insurance. One potential contributor is perceived unwillingness of surgeons and hospitals to accept underinsured patients. We used administrative data to examine the payer mix for select inpatient orthopaedic surgical procedures at all hospitals within a single region, hypothesizing that the delivery of orthopaedic surgery to Medicaid beneficiaries varies highly at the hospital level. Methods Using administrative data, we analyzed inpatient hospitalizations for elective cases (total knee or hip arthroplasty; spinal decompression or fusion) and trauma cases (hip hemiarthroplasty; femoral or tibial and fibular fracture repair) among 22 hospitals in a single region from 2011 to 2016 for patients who were 18 to 64 years of age. The primary outcome was the percentage of each hospital's caseload with Medicaid listed as the primary payer. The secondary outcome measured each hospital's Medicaid percentage against the percentage of Medicaid-insured individuals within 10 miles of the hospital (Medicaid share ratio), using a ratio of 1 as a benchmark. To quantify variation, we calculated a weighted coefficient of variation of the Medicaid share ratio for all cases combined, elective cases only, and trauma cases only. Results For all cases (n = 19,204), the mean percentage of Medicaid-funded surgical procedures was 7.6% (range, 0.2% to 57.3%). The mean Medicaid share ratio was 1.0 (range, 0.05 to 4.20). Across 22 hospitals, the weighted coefficient of variation for Medicaid share was 69, indicating very high variation. For elective cases alone, the mean percentage of Medicaid-funded surgical procedures was 5.5% (range, 0.2% to 64.6%). The mean Medicaid share ratio was 0.71 (range, 0.05 to 4.73), and the weighted coefficient of variation was 93. For trauma cases alone, Medicaid-funded surgical procedures were 14.7% (range, 0.0% to 35.7%). The mean Medicaid share ratio was 2.0 (range, 0 to 3.93), and the weighted coefficient of variation was 34. Conclusions Delivery of care was highly variable when benchmarking against the insurance composition of each hospital's surrounding community. Although generalizability to other regions is limited, our findings support previously asserted notions that delivery of orthopaedic care may differ on the basis of socioeconomic markers (such as insurance status). If not addressed, these inequities may exacerbate existing racially and socioeconomically based disparities in care.

Background The β-lactamase inhibitor relebactam can restore imipenem activity against imipenem-nonsusceptible gram-negative pathogens. We evaluated imipenem/relebactam for treating imipenem-nonsusceptible infections. Methods Randomized, controlled, double-blind, phase 3 trial. Hospitalized patients with hospital-acquired/ventilator-associated pneumonia, complicated intraabdominal infection, or complicated urinary tract infection caused by imipenem-nonsusceptible (but colistin- and imipenem/relebactam-susceptible) pathogens were randomized 2:1 to 5–21 days imipenem/relebactam or colistin+imipenem. Primary endpoint: favorable overall response (defined by relevant endpoints for each infection type) in the modified microbiologic intent-to-treat (mMITT) population (qualifying baseline pathogen and ≥1 dose study treatment). Secondary endpoints: clinical response, all-cause mortality, and treatment-emergent nephrotoxicity. Safety analyses included patients with ≥1 dose study treatment. Results Thirty-one patients received imipenem/relebactam and 16 colistin+imipenem. Among mITT patients (n = 21 imipenem/relebactam, n = 10 colistin+imipenem), 29% had Acute Physiology and Chronic Health Evaluation II scores >15, 23% had creatinine clearance, Imipenem/relebactam (IMI/REL) is a suitable treatment option for serious gram-negative infections, including those caused by carbapenem-nonsusceptible pathogens in high-risk patients. IMI/REL may be preferable to colistin-based therapy, given comparable efficacy but IMI/REL’s significantly lower nephrotoxicity and improved overall tolerability.

Aim Flow redistribution is not uncommonly performed as a treatment strategy to optimize delivery of radioembolization particles to the liver. We quantitatively evaluated the effect of vessel embolization to promote flow redistribution when performing selective internal radiation therapy (SIRT) for liver metastases, and assessed long-term outcomes of treatment. Materials and Methods One hundred and fifty-eight SIRT procedures over an 8-year period were retrospectively reviewed. Twenty-three patients who underwent partial/whole embolization of the left hepatic artery were compared to a control group of 18 patients who did not receive any hepatic embolization as part of their work up. Counts were measured for each patient on both the post-99mTcMAA injection, and the post-90Y microspheres injection imaging. Recurrence and survival rates were also measured. Results A statistically significant shift in the right:left ratio between planning and treatment procedures was seen in patients who had vessel embolization in favor of the embolized lobe (p = 0.014). There was no significant difference in the time to recurrence in the embolized lobes versus the nonembolized lobes. No significant difference in overall survival was detected between the two cohorts. Conclusion To facilitate safe whole liver treatment, it is sometimes necessary to partially or completely occlude main or accessory hepatic arteries. This study shows that the success of flow redistribution strategies can be quantitatively measured, and there is no adverse impact on time to recurrence or overall survival outcomes.

Accurate image quantification requires accurate calibration of the detector and is vital if dosimetry is to be performed in molecular radiotherapy. A dependence on the position of calibration has been observed in single photon emission computed tomography images when attenuation correction (AC) and scatter correction are applied. This work investigates the origin of this dependence in single photon emission computed tomography scans of phantom inserts filled with Lu solution. A 113 ml sphere and inserts representing a mathematical model of a spleen and an anatomical model of a patient spleen were imaged at the centre and edge of elliptical phantoms. For these inserts, the difference in calibration factor between the positions was around 10% for images reconstructed with AC and triple energy window scatter correction. A combination of experimental imaging and Monte Carlo simulation was used to isolate possible causes due to imaging or reconstruction in turn. Inconsistent application of AC between different reconstruction systems was identified as the origin of the positional dependence.

Background As the older population increases, more older people are exposed to trauma. Frailty can be used to highlight patients at risk of a poorer outcome. Objective The objectives of this study were to compare 2 frailty measures with regard to concordance, floor and ceiling effects, and construct and predictive validity and to determine which is more valid and clinically applicable in a critically ill trauma population. Design This was a prospective observational study. Methods Patients were included if admitted to an intensive care unit (ICU) under a trauma medical unit and ≥ 50 years old. Frailty was determined using 2 frailty measures, the Frailty Phenotype (FP) and Clinical Frailty Scale (CFS). Results One hundred people were enrolled; their mean age was 69.2 years (SD = 10.4) and 81% had major trauma (as determined with the Injury Severity Score). Frailty was identified with the FP in 22 participants and with the CFS in 13 participants. The 2 frailty measures had an excellent correlation (Spearman rank correlation coefficient = 0.77; 95% confidence interval = 0.66–0.85). Both the FP and the CFS had large floor effects but no ceiling effects. The FP and CFS showed construct validity, with frailty being significantly associated with increasing age, requiring an aid to mobilize, and more falls and hospital admissions. Frailty on the FP was predictive of ICU and hospital mortality, whereas frailty on the CFS was predictive of hospital mortality. Limitations The limitations of this study include the use of a single site, small sample size, and collection of frailty measures retrospectively. Conclusions Measuring frailty in a trauma ICU population was feasible, with excellent correlation between the 2 frailty measures. Both showed aspects of construct and predictive validity; however, the FP identified frailty in more participants and was associated with more comorbidities and higher mortality at ICU discharge. Therefore, the FP might be more clinically relevant in this population.

ObjectiveEarly-onset colorectal cancer (CRC) is increasing in many developed countries. Type 2 diabetes mellitus has increased substantially in younger adults; however, its role in early-onset CRC remains unidentified.DesignWe conducted a claims-based nested case-control study using IBM® MarketScan® Commercial Database (2006-2015). Incident early-onset CRC diagnosed at ages 18-49 were identified by ICD-9-CM diagnosis code, and the first coded diagnostic pathology date was assigned as the index date. Controls were frequency matched with cases. Type 2 diabetes, stratified by severity, was identified through ICD-9-CM using the Klabunde algorithm. Multivariate logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals (Cls).ResultsA total of 6001 early-onset CRC and 52104 controls were included. Type 2 diabetes was associated with an increased risk of early-onset CRC (5.0% in cases vs. 3.7% in controls; OR 1.24; 95% CI 1.09 to 1.41). The positive association was more pronounced for uncontrolled (OR 1.37; 95% CI 1.12 to 1.67) or complicated (OR 1.59; 95% CI 1.08-2.35) type 2 diabetes compared to controlled diabetes (OR 1.13; 95% CI 0.94 to 1.36). The positive association was driven by proximal (OR 1.35; 95% CI 1.03 to 1.77) and distal (OR 1.67; 95% CI 1.30 to 2.15) colon cancer but not rectal cancer.ConclusionsIndividuals with type 2 diabetes have a higher risk of early-onset CRC, with stronger associations for uncontrolled/complicated diabetes. The rising prevalence of type 2 diabetes among younger adults in the US may partially contribute to the increasing incidence of early-onset CRC.

Primary ciliary dyskinesia is an incurable, rare, inherited, chronic condition. Treatment includes regular clearing of airway mucus, aggressive treatment of infections and management of hearing loss. Caregiver burden has not been explored, hence we interviewed 18 English speaking mothers and 6 English speaking fathers of children under 6 years who were diagnosed with PCD around the world. The parents described how the child’s diagnosis, treatment regimen, and health status impacted their life. They discussed the impact of the COVID-19 pandemic and they talked about the different ways they cope with challenges that arise. The need for integrated social care is discussed.

Locally advanced rectal cancer has a rising global incidence. Over the last 4 decades, advances first in surgery and later in radiotherapy and chemoradiotherapy have improved outcomes, particularly with regard to local recurrence. Unfortunately, distant metastases remain a significant problem. In clinical trials of patients with stage II and III disease, distant relapse occurs in 25% to 30% of patients regardless of the treatment approach. Recent phase 3 trials have therefore focused on intensification of systemic therapy for localized disease, with an aim of reducing the distant relapse rate. Early results of trials of total neoadjuvant therapy with combination systemic therapy provided in the neoadjuvant setting are promising; for the first time, a significant improvement in the rate of distant relapse has been noted. Longer-term follow-up is eagerly awaited. On the other hand, trimodal therapy with chemotherapy, radiotherapy, and surgery is toxic. Several trials are currently assessing the feasibility of a watch-and-wait approach, omitting surgery in those with complete response to neoadjuvant treatment, in an attempt to reduce the burden of treatment on patients. The future for rectal cancer patients is likely to be highly personalized, with more intense approaches for high-risk patients and omission of unnecessary therapy for those whose disease responds well to initial treatment. Biomarkers such as circulating tumor DNA will help to more accurately stratify patients into risk groups. Improvements in survival and quality of life are expected as the results of ongoing research become available throughout the next decade. (C) 2021 Published by Elsevier Inc. All rights reserved.

Background The ongoing SURPASS trial (NCT04044859) evaluates safety and efficacy of next-generation ADP-A2M4CD8 SPEAR T-cells co-expressing the CD8α co-receptor with the engineered MAGE-A4c1032T cell receptor (TCR). Methods First-in-human trial in HLA-A*02 positive patients (pts) with advanced cancers expressing MAGE-A4 antigen by immunohistochemistry. Eligible pts undergo apheresis, T-cells are isolated, transduced with a Lentiviral vector containing the MAGE-A4c1032 TCR and CD8α co receptor, and expanded. Expansion, transduction level, cellular composition and function of the manufactured product (MP) are assessed in vitro. Prior to infusion, pts receive lymphodepletion with fludarabine 30 mg/m2/day for 4 days and cyclophosphamide 600 mg/m2/day for 3 days. Results As of 16 July 2020, 5 pts (1 with MRCLS, 2 with esophagogastric junction [EGJ] cancers, 1 with ovarian cancer, and 1 with head and neck cancer) were treated with ADP-A2M4 CD8 (range ~1 to 5.7 billion transduced cells). No DLTs or SAEs have been reported. To date, 1 pt with EGJ cancer had a partial response (PR per RECIST) and has had progression-free survival >6 months. One pt with head and neck cancer also had a PR. All other pts have had best overall response of stable disease.MP expanded by an average of 15.3 fold during manufacturing (range 5.9 to 25.6-fold). On average, 43% of T-cells in the MP expressed the TCR (range 23 to 63%). The fraction of CD4+ cells in the final MP varied (range 45 to 84%). Co-expression of the MAGE-A4 TCR and CD8α in CD4+ T-cells in the patient MP enabled CD4+ T-cells to kill tumor target cells directly in vitro. MAGE-A4 expression in tumor biopsies varied (H-score range 55 to 300). Transduced T-cells were detected in peripheral blood of all pts. IFN-gamma increased transiently in the serum of 1 pt who responded. Conclusions ADP-A2M4CD8 SPEAR T-cells have shown an acceptable safety profile and pts with EGJ cancer and head and neck cancer have demonstrated evidence of antitumor activity. Translational data and early clinical results indicate that co-expression of the CD8α co-receptor on CD4+ SPEAR T-cells may increase the potency of the product by conferring additional killing activity to the helper T-cell subset. This dose escalation trial is ongoing and updated clinical and translational data will be presented. Trial Registration NCT04044859 Ethics Approval The trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines and was approved by local authorities. An independent ethics committee or institutional review board approved the clinical protocol at each participating center. All the patients provided written informed consent before study entry.

Background T-cells attributes for adoptive cell therapy of patients with advanced cancer can be optimized during ex vivo expansion culture. Autologous TCR-engineered T-cells targeting the MAGE-A4 antigen with Specific Peptide Enhanced Affinity Receptors (SPEAR T-cells) have shown promise in the clinic.1 The highly variable leukocyte material obtained from individual patients during apheresis can present a manufacturing challenge for autologous T-cell therapies. The degree of ex vivo expansion and the functional attributes of the expanded T-cell product impact therapeutic efficacy and can be suboptimal for some patient apheresis material. Both TCR and cytokine growth factor signals used for ex vivo T-cell expansion promote robust activation of AKT (Protein Kinase B) signaling, which drives T-cell activation, proliferation, and terminal differentiation. It is hypothesized that inhibition of AKT signaling during T-cell expansion may uncouple proliferation and terminal differentiation, leading to the generation of less differentiated T-cells that may have functional benefit in vivo.2 3 Methods We evaluated use of an AKT inhibitor during SPEAR T-cell manufacturing using leukocytes from healthy donors and patients with advanced solid cancers. Results AKT inhibition resulted in the generation of a more consistent expansion and phenotype of the final T-cell product. This was observed using two SPEAR T-cell constructs, ADP-A2M4 and ADP-A2M4CD8. Ex vivo SPEAR T-cell expansion in the presence of an AKT inhibitor generated CD8+ T-cells that maintained a less differentiated phenotype (based on CCR7+CD45RA+ and CD62L+ expression). AKT inhibition was associated with enhanced antigen-specific responses of SPEAR T-cells in vitro, including effector cytokine production, target-cell killing, ability to proliferate in response to prolonged antigen-stimulation and maintenance of cytotoxic activity following antigen re-stimulation. Conclusions We plan to introduce AKT inhibition into the GMP manufacturing process, and evaluate the efficacy of the resulting products in ongoing clinical studies. Acknowledgements We are extremely grateful to the patients, who were previously enrolled in our clinical trials, and healthy donors for their consent for R&D studies. This was a collaborative cross-functional project, and we are grateful for the contributions of the following Scientists: Garth Hamilton, Adel Toth, Abigail Kay, Sophie Badie, Josh Griffiths, Kaushik Sarkar, Anoop Chandran. Ethics Approval The experimental study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines and was approved by local authorities. An independent ethics committee or institutional review board approved the clinical protocol at each participating center. All the patients provided written informed consent before study entry. References Hong DS, Van Tine BA, Olszanski AJ, et al, Phase 1 dose escalation and expansion trial to assess safety and efficacy of ADP-A2M4 in advanced solid tumors. J Clin Oncol 2020;38;A102. Klebanoff C, Crompton J, Leonardi A, et al. Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy. JCI Insight 2017;2:e95103. van der Waart A, van de Weem N, Maas F, et al. Inhibition of Akt signaling promotes the generation of superior tumor-reactive T cells for adoptive immunotherapy. Blood. 2014;124;3490-3500

Anthracycline-based chemotherapy is a common treatment for cancer patients. Because it is delivered intravenously, endothelial cells are exposed first and to the highest concentrations, prior to diffusion to target cells. Not surprisingly, vascular dysfunction is a consequence of anthracycline therapy. While chemotherapy-induced endothelial damage at administration sites has been investigated, the effects of lower doses encountered by distant microvascular networks has not. The aim of this study was to investigate the impact of epirubicin, a widely used anthracycline, on healthy endothelial cells to elucidate its effects on microvascular physiology.Here, endothelial cells were briefly exposed to low doses of epirubicin to recapitulate levels in circulation following dilution in the blood and compound half-life in circulation. Both immediate and prolonged responses to treatment were assessed to determine changes in endothelial function.Epirubicin caused a decrease in proliferation and viability in hUVEC, with lower doses resulting in a senescent phenotype in a large proportion of cells, accompanied by a significant increase in pro-inflammatory cytokines and a significant decrease in metabolic activity. Epirubicin exposure also impaired endothelial function with delayed wound closure, reduced angiogenic potential and increased monolayer permeability downstream of VE-cadherin internalization. Primary lung endothelial cells obtained from epirubicin-treated mice similarly demonstrated reduced viability and functional impairment. In vivo, epirubicin treatment resulted in persistent reduction in lung vascular density and significantly increased infiltration of myeloid cells.Modulation of endothelial status and inflammatory tissue microenvironment observed in response to low doses of epirubicin may predict risk for long-term secondary pathologies associated with chemotherapy.

This paper develops a classification of investor risks and surveys 51 private investors and financiers in the power sector in Sub-Saharan Africa. The paper aims for a better understanding of what can be done to attract private solutions to fill the investment gap. It finds that the average investor assigns more weight to power sector policy and regulatory framework risks than to the wider sector and country context risks. And, despite many challenges, investors perceive three segments as ready for private solutions in Sub-Saharan Africa: power generation, off-grid electrification, and mini-grids. Investors see lower readiness in distribution, transmission, and retail. The paper finds that the average investor is forward-looking, as neither the track record of the power sector nor the firm’s personal track record is as important as the growth potential in the market. The paper uses the findings to reality-check data-based measures of regulatory readiness, namely the Regulatory Indicators for Sustainable Energy and Power Sector Reform Index and analyzes which elements correlate best with investor sentiment to optimize and streamline these indexes accordingly. The results provide important lessons for governments and development partners to devise appropriate de-risking instruments tailored to the risks that matter most to investors.

Background In phase 3 MODIFY I/II trials, bezlotoxumab significantly reduced recurrence of Clostridioides (Clostridium) difficile infection (rCDI) over 12 weeks. Choice of CDI antibacterial treatment may affect CDI-related outcomes; therefore, this prespecified analysis assessed if the magnitude of bezlotoxumab-induced rCDI reduction was influenced by the antibiotic administered. Methods In MODIFY I/II (NCT01241552/NCT01513239), participants received a single infusion of bezlotoxumab (10 mg/kg) or placebo during anti-CDI treatment. Using pooled data from MODIFY I/II, initial clinical cure (ICC) and rCDI were assessed in metronidazole-, vancomycin-, and fidaxomicin-treated subgroups. Results Of 1554 participants in MODIFY I/II, 753 (48.5%) received metronidazole, 745 (47.9%) vancomycin, and 56 (3.6%) fidaxomicin. Fewer participants receiving metronidazole had a prior CDI episode in the previous 6 months (12.9%) or ≥1 risk factor for rCDI (66.0%) vs participants receiving vancomycin (41.2% and 83.6%, respectively) and fidaxomicin (55.4% and 89.3%, respectively). ICC rates were similar in the bezlotoxumab (metronidazole, 81.0%; vancomycin, 78.5%; fidaxomicin, 86.7%) and placebo groups (metronidazole, 81.3%; vancomycin, 79.6%; fidaxomicin, 76.9%). In placebo-treated participants, the rCDI was lower in the metronidazole subgroup vs the vancomycin and fidaxomicin subgroups (metronidazole, 28.0%; vancomycin, 38.4%; fidaxomicin, 35.0%). When analyzed by subsets based on history of CDI, rCDI rates were similar in the metronidazole and vancomycin groups. rCDI rates were lower in all antibiotic subgroups for bezlotoxumab vs placebo (metronidazole: rate difference [RD], –9.7%; 95% confidence interval [CI], –16.4% to –3.1%; vancomycin: RD, –15.4%; 95% CI, –22.7% to –8.0%; fidaxomicin: RD, –11.9%; 95% CI, –38.1% to 14.3%). Conclusion Bezlotoxumab reduces rCDI vs placebo in participants receiving metronidazole and vancomycin, with a similar effect size in participants receiving fidaxomicin.

ObjectiveFactors that lead to metabolic dysregulation are associated with increased risk of early-onset colorectal cancer (CRC diagnosed under age 50). However, the association between metabolic syndrome (MetS) and early-onset CRC remains unexamined.DesignWe conducted a nested case–control study among participants aged 18–64 in the IBM MarketScan Commercial Database (2006–2015). Incident CRC was identified using pathologist-coded International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, and controls were frequency matched. MetS was defined as presence of ≥3 conditions among obesity, hypertension, hyperlipidaemia and hyperglycaemia/type 2 diabetes, based on ICD-9-CM and use of medications. Multivariable logistic regressions were used to estimate ORs and 95% CIs.ResultsMetS was associated with increased risk of early-onset CRC (n=4673; multivariable adjusted OR 1.25; 95% CI 1.09 to 1.43), similar to CRC diagnosed at age 50–64 (n=14 928; OR 1.21; 95% CI 1.15 to 1.27). Compared with individuals without a metabolic comorbid condition, those with 1, 2 or ≥3 conditions had a 9% (1.09; 95% CI 1.00 to 1.17), 12% (1.12; 95% CI 1.01 to 1.24) and 31% (1.31; 95% CI 1.13 to 1.51) higher risk of early-onset CRC (ptrend ConclusionsMetabolic dysregulation was associated with increased risk of early-onset CRC, driven by proximal and distal colon cancer, thus at least in part contribute to the rising incidence of early-onset CRC.

Background The optimal management of impaired knee joint function in patients with cerebral palsy (CP) remains a significant and ongoing challenge in paediatric orthopaedic surgery. Research question What are the clinical and functional outcomes after operative and non-operative orthopaedic interventions for knee joint impairment in patients with CP? Methods This systematic review and meta-analysis of orthopaedic interventions for the management of knee joint impairment in paediatric CP patients evaluated study-level data in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. We performed searches of the following electronic databases from their dates of inception to November 2019: Medline (Ovid), Embase (Ovid) and Pubmed. We extracted mean differences in pre-operative and post-operative measurements for the following outcomes: minimum knee flexion in stance; knee flexion at initial contact; maximum knee flexion in swing; range of motion; popliteal angle; fixed flexion deformity angle; and mean pelvic tilt. Results Sixty-nine retrospective cohort studies, prospective cohort studies and RCTs comprising 2991 patients were included with 4578 knees analysed. Included studies were of sufficient quality as assessed by the MOOSE checklist. Operative interventions showed significant improvement in knee flexion at initial contact, knee flexion in stance, range of motion, popliteal angle and fixed flexion deformity which were comparable when subgrouped according to operative technique. In contrast, non-operative techniques and botulinum toxin injection did not confer significant improvements. Operative interventions for knee joint impairment led to increased mean pelvic tilt and reduced maximum knee flexion in swing. Significance This review provides strong evidence that operative interventions for the management of knee joint impairment in cerebral palsy patients improve knee kinematics and clinical examination findings.

Understanding how agricultural practices alter biogeochemical cycles is vital for maintaining land productivity, food security, and other ecosystem services such as carbon sequestration. However, these are complex, highly coupled long-term processes that are difficult to observe or explore through empirical science alone. Models are required that capture the main anthropogenic disturbances, whilst operating across regions and long timescales, simulating both natural and agricultural environments, and shifts among these. Many biogeochemical models neglect agriculture or interactions between carbon and nutrient cycles, which is surprising given the scale of intervention in nitrogen and phosphorus cycles introduced by agriculture. This gap is addressed here, using a plant-soil model that simulates integrated soil carbon, nitrogen and phosphorus (CNP) cycling across natural, semi-natural and agricultural environments. The model is rigorously tested both spatially and temporally using data from long-term agricultural experiments across temperate environments. The model proved capable of reproducing the magnitude of and trends in soil nutrient stocks, and yield responses to nutrient addition. The model has potential to simulate anthropogenic effects on biogeochemical cycles across northern Europe, for long timescales (centuries) without site-specific calibration, using easily accessible input data. The results demonstrate that weatherable P from parent material has a considerable effect on modern pools of soil C and N, despite significant perturbation of nutrient cycling from agricultural practices, highlighting the need to integrate both geological and agricultural processes to understand effects of land-use change on food security, C storage and nutrient sustainability. The results suggest that an important process or source of P is currently missing in our understanding of agricultural biogeochemical cycles. The model could not explain how yields were sustained in plots with low P fertiliser addition. We suggest that plant access to organic P is a key uncertainty warranting further research, particularly given sustainability concerns surrounding rock sources of P fertiliser.

Phosphorus is a critical nutrient in sustaining food production. In agricultural systems, application of P fertilizers has significantly increased since the green revolution to become common practi...

The cycling of carbon within the earth system is intrinsically linked with major nutrients, notably nitrogen and phosphorus, due to the tendency of these elements to limit the productivity of terre...

Guidelines recommend surveillance after resection of colorectal cancer (CRC), but rates of adherence to surveillance are variable and have not been studied at National Cancer Institute (NCI)‐designated Comprehensive Cancer Centers. The aim of this study was to determine rates of adherence to standard postresection CRC surveillance recommendations including physician visits, carcinoembryonic antigen (CEA), computed tomography (CT), and colonoscopy after CRC resection at three NCI‐designated centers. Data on patients with resected CRC from 2010 to 2017 were reviewed. Adherence to physician visits was defined as having at least two visits within 14 months after surgical resection. CEA adherence was defined as having at least four CEA levels drawn within 14 months. CT and colonoscopy adherence were defined as completing each between 10 and 14 months from surgical resection. Chi‐square test and logistic regression analyses were performed for overall adherence and adherence to individual components. A total of 241 CRC patients were included. Overall adherence was 23%. While adherence to physician visits was over 98%, adherence to CEA levels, CT, and colonoscopy were each less than 50%. Center was an independent predictor of adherence to CEA, CT, and/or colonoscopy. Stage III disease predicted CT adherence, while distance traveled of 40 miles or less predicted colonoscopy adherence. Overall adherence to postresection CRC guideline‐recommended care is low at NCI‐designated centers. Adherence rates to surveillance vary by center, stage, and distance traveled for care. Understanding factors associated with adherence is critical to ensure CRC patients benefit from postresection surveillance.

Background The intensive care unit mobility scale (IMS) is reliable, valid and responsive. Establishing the minimal important difference (MID) of the IMS is important in order to detect clinically significant changes in mobilization. Objective To calculate the MID of the IMS in intensive care unit patients. Methods Prospective multi center observational study. The IMS was collected from admission and discharge physiotherapy assessments. To calculate the MID we used; anchor based methods (global rating of change) and two distribution-based methods (standard error of the mean and effect size). Results We enrolled 184 adult patients; mean age 62.0 years, surgical, trauma, and medical. Anchor based methods gave a MID of 3 with area under the curve 0.94 (95% CI 0.89-0.97). The two distribution based methods gave a MID between 0.89 and 1.40. Conclusion These data increase our understanding of the clinimetric properties of the IMS, improving its utility for clinical practice and research.

We evaluated the safety and activity of autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) recognizing an HLA-A2–restricted NY-ESO-1/LAGE1a–derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1c259T cells). Confirmed antitumor responses occurred in 50% of patients (6/12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1c259T cells were present postinfusion in all patients and persisted for at least 6 months in all responders. Most of the infused NY-ESO-1c259T cells exhibited an effector memory phenotype following ex vivo expansion, but the persisting pools comprised largely central memory and stem-cell memory subsets, which remained polyfunctional and showed no evidence of T-cell exhaustion despite persistent tumor burdens. Next-generation sequencing of endogenous TCRs in CD8+ NY-ESO-1c259T cells revealed clonal diversity without contraction over time. These data suggest that regenerative pools of NY-ESO-1c259T cells produced a continuing supply of effector cells to mediate sustained, clinically meaningful antitumor effects. Significance: Metastatic synovial sarcoma is incurable with standard therapy. We employed engineered T cells targeting NY-ESO-1, and the data suggest that robust, self-regenerating pools of CD8+ NY-ESO-1c259T cells produce a continuing supply of effector cells over several months that mediate clinically meaningful antitumor effects despite prolonged exposure to antigen. Cancer Discov; 8(8); 944–57. ©2018 AACR. See related commentary by Keung and Tawbi, p. 914. This article is highlighted in the In This Issue feature, p. 899

Valuing amenity trees is important for calculating loss of amenity and replacement value following wilful or negligent damage, and for several aspects of urban forest management: planning, budget setting and decision-making. Capital Asset Value for Amenity Trees (CAVAT) is a tool for valuing amenity trees; it was first presented publicly in 2003. It includes two methods: the Full Method, which is used to provide a compensation replacement value for single trees; and the Quick Method, which is used to determine the value of a population of trees as an asset, for asset management purposes. CAVAT is widely adopted across the UK within local authority tree departments, and by major land-holding and transport organisations. It is also incorporated into the Joint Mitigation Protocol for use in the assessment of subsidence cases. This paper presents CAVAT for the first time in a formal publication. It describes the uses for which it has been designed, it comprehensively describes the methodology and show...

Background: SIRT is a globally licensed technique of Radio-Embolization (RE) of hepatic tumors via intra-arterial infusion of β-particle emitting Yttrium-90 (Y-90) radio-labelled microspheres. It increases response rates and hepatic time to progression in metastatic colorectal cancer when used in combination with 5FU/Oxaliplatin (FOLFOX) chemotherapy with acceptable toxicity profile. FOLFOX gives a radio-sensitizing effect and also controls disease outside the liver. Breast cancer liver metastases (BCLM) patients often have extra-hepatic disease and respond to multiple lines of systemic therapy and SIRT is infrequently used. Methods and patients Between 2010 and 2016 we treated 25 BCLM patients with Y-90 SIRT. Receptor status: 20 ER+ve/HER-2 -ve, 3 ER-ve/HER-2 +ve, 2 triple -ve. Eleven patients had liver only disease with 14 also having known extra-hepatic disease. Average number of previous lines of therapy in metastatic setting: chemotherapy = 2.4; endocrine = 1. Sixty-four % patients had prior Capecitabine (n=16); 12% platinum (n=3, all Carboplatin). Twenty patients received chemotherapy with SIRT: 17 had modified FOLFOX6 (Oxaliplatin/bolus 5FU day1, infusional 5FU day 1-3 (46 hrs); 3 patients had Modified de Gramont style 5FU alone. Five patients had no chemotherapy. Sir-spheres were inserted on day 2 of FOLFOX with the 5FU infusion pump continuing to day 3. Further 2-weekly FOLFOX chemo cycles were at clinician's discretion: average number delivered 3.8. Four patients had the liver treated in two halves, approximately 6 weeks apart. One patient received SIRT only to half the liver. Patients were imaged with PET-CT/CT before and 2-3 months after SIRT. Retrospective case note review was performed and data correlated to evaluate tumor response (RR); hepatic and extra hepatic progression free survival (HPFS and EHPFS) and overall survival (OS). Accurate toxicity data was not recorded. Results Hepatic CT response rates: PR 56% (n=14), SD 28% (n=7) and PD 16% (n=4). Hepatic PET response rates: CR 32% (n=8), PR 40% (n=10), SD 12% (n=3), PD 16%(n=4). (Overall PET liver disease control rate = 84%). Eight patients (32%) had extra-hepatic PD at first assessment. Of them, 4 had PR, 2 SD and 2 PD in the liver at that assessment. Two HER-2 +ve patients had brain metastases as first sign of PD within 75 days, an area not previously screened. Of 16 pre-treated with Capecitabine, liver CT response rates: 62.5% PR, 18.75% SD (n=10,3). Post SIRT/FOLFOX, average number of therapy lines: 2 for chemo and 0.75 for endocrine, with 8 patients still alive at time of censoring. Median OS: 766 HPFS: 210 days (CI 140-286). Median EHPFS in patients with extra-hepatic disease: 152 days (CI 96-636). Conclusions SIRT with FOLFOX in previously treated BCLM patients produces high response rates, excellent tumor control and time to progression in the liver with good overall survival. It does not seem to decrease the ability to give further lines of chemotherapy and can be considered as an option for breast cancer patients with liver metastases. Citation Format: Wilson G, Mullamitha S, Bentley D, Bell J, Mullan D, Carter L, Chittalia A, Howell S, Laasch H-U, Westwood T, Jeans S, Tipping J, Ryder D, Farquharson F, Arumugam P, Sheen A, Rajashanker B, Armstrong A, Misra V, Manoharan P, Lawrance J. Selective internal radiation therapy (SIRT) with Yttrium-90 resin microspheres and FOLFOX/5FU chemotherapy in pre-treated breast cancer patients with liver metastases: A retrospective analysis of response rates, times to progression and survival of patients treated in Manchester UK between 2010 and 2016 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-14-06.

Pre-clinical and epidemiology studies suggest that antibodies directed at C. difficile toxins protect against recurrence of C. difficile infection (CDI). Human monoclonal antibodies (MAb) targeting...

Objective: Can a comprehensive, explicitly directive evidence-based guideline for all therapies that might affect the major morbidities of very low-birth-weight (VLBW) infants help a neonatal intensive care unit (NICU) further improve generally favorable morbidity rates? Can Antifragility principles of provider adaptive growth from stressors, enhanced infant risk assessment and adherence to effective therapies minimize unproven treatments and reduce all morbidities? Study Design: Prospectively planned observational trial in VLBW infants: control group born October 2011 to September 2013 and study group October 2013 to September 2015. Multi-disciplinary evidence-based review assigned all NICU treatments into one of four distinct categories: (1) always employ this therapy for VLBW infants, (2) never use this therapy, (3) employ this questionable therapy thoughtfully, only in certain circumstances and (4) this therapy has insufficient evidence of efficacy and safety. Extensive staff education emphasized evidence-based potentially better practice (PBP) selection with compliance checks, appreciation of intertwined co-morbidities and prioritizing infant risk reduction strategies. Results: Control included 221 infants, mean (s.d.) age 29 (2.6) weeks, birth weight 1129 (257) g and Study included 197 infants, 29 (2.7) weeks, 1093 (292) g. One hundred and four distinct therapies were placed into categories 1 to 4, with 32 specific compliance checks. Overall mean compliance with the process checks during the second era was 70%, high: 100% (exclusive breast milk use), low: 24% (correct pulse oximetry alarm settings). Morbidity and mortality rates did not significantly change during the second era. Conclusions: In our NICU with favorable morbidity rates, an expanded effort using a comprehensive therapy guideline for VLBW infants did not further improve outcomes. We need deeper understanding of continuous quality improvement (CQI) fundamentals, therapy compliance, co-morbidity relationships and enhanced sensitivity of risk assessment. Our innovative Antifragility PBP guideline could be useful to other NICUs seeking improvement in VLBW infant morbidities, as we offer a reasoned and concise template of a broad array of therapies categorized efficiently for transparency and review, designed to enhance responsible CQI decision-making.

Atherosclerosis is initiated by cholesterol entry into arteries that triggers chronic immune-inflammatory lesions in the vessels. Early lesions are clinically insignificant but advanced complex lesions and vulnerable rupture prone lesions impact on quality of life and can be life threatening. Rupture of vulnerable atherosclerotic lesions initiates thrombotic occlusion of vital arteries precipitating heart attacks and strokes that remain major killers globally despite therapeutic use of statins to lower blood cholesterol levels. Conventional B2 cells are proatherogenic whereas peritoneal Bla cells are atheroprotective. Depletion of B2 cells by administration of mAb to CD20 or to BAFF receptor or in BAFF receptor-deficient mice ameliorates atherosclerosis. B2 cells may promote atherosclerosis by production of IgG, secretion of proinflammatory cytokine TNFα and activation of CD4 T cells. Together these B2 cell mechanisms contribute to generation of rupture-prone vulnerable atherosclerotic plaques characterised by large necrotic cores. In contrast, peritoneal Bla cells protect against atherosclerosis by secretion of natural IgM that scavenges apoptotic cells and oxidised LDL and reduces necrotic cores in atherosclerotic lesions. These atheroprotective effects can be further increased by stimulating Bla cells by administration of apoptotic cells, liposomes of phosphatidylserine abundant on surfaces of apoptotic cell, by mAb to TIM1, a phosphatidylserine receptor expressed by B1a cells and by TLR4-MyD88 activation. Experimental studies of atherosclerosis in mouse models indicate that reductions in atherogenic B2 cells and/or activation of atheroprotective B1a cells protects against atherosclerosis development, findings which have potential for clinical translation to reduce risks of deaths from heart attacks and strokes.

[Hodgson CL, Tipping CJ (2016) Physiotherapy management of intensive care unit-acquired weakness. Journal of Physiotherapy 63: 4–10]

Background In the RESTORE-IMI 2 trial, imipenem/cilastatin/relebactam (IMI/REL) was non-inferior to PIP/TAZ for treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) in the primary endpoint of Day 28 all-cause mortality (D28 ACM) and the key secondary endpoint of clinical response (CR) at early follow-up (EFU; 7-14 d after end of therapy). We performed a multivariate regression analysis to determine independent predictors of treatment outcomes in this trial. Methods Randomized, controlled, double-blind, phase 3, non-inferiority trial comparing IMI/REL 500 mg/250 mg vs PIP/TAZ 4 g/500 mg, every 6 h for 7-14 d, in adult patients (pts) with HABP/VABP. Stepwise-selection logistic regression modeling was used to determine independent predictors of D28 ACM and favorable CR at EFU, in the MITT population (randomized pts with ≥1 dose of study drug, except pts with only gram-positive cocci at baseline). Baseline variables (n=19) were pre-selected as candidates for inclusion (Table 1), based on clinical relevance. Variables were added to the model if significant (p < 0.05) and removed if their significance was reduced (p > 0.1) by addition of other variables. Results Baseline variables that met criteria for significant independent predictors of D28 ACM and CR at EFU in the final selected regression model are in Fig 1 and Fig 2, respectively. As expected, APACHE II score, renal impairment, elderly age, and mechanical ventilation were significant predictors for both outcomes. Bacteremia and P. aeruginosa as a causative pathogen were predictors of unfavorable CR, but not of D28 ACM. Geographic region and the hospital service unit a patient was admitted to were found to be significant predictors, likely explained by their collinearity with other variables. Treatment allocation (IMI/REL vs PIP/TAZ) was not a significant predictor for ACM or CR; this was not unexpected, since the trial showed non-inferiority of the two HABP/VABP therapies. No interactions between the significant predictors and treatment arm were observed. Conclusion This analysis validated known predictors for mortality and clinical outcomes in pts with HABP/VABP and supports the main study results by showing no interactions between predictors and treatment arm. Table 1. Candidate baseline variables pre-selected for inclusion Figure 1. Independent predictors of greater Day 28 all-cause mortality (MITT population; N=531) Figure 2. Independent predictors of favorable clinical response at EFU (MITT population; N=531) Disclosures Robert Tipping, MS, Merck & Co., Inc. (Employee, Shareholder) Jiejun Du, PhD, Merck & Co., Inc. (Employee, Shareholder) Maria C. Losada, BA, Merck & Co., Inc. (Employee, Shareholder) Michelle L. Brown, BS, Merck & Co., Inc. (Employee, Shareholder) Katherine Young, MS, Merck & Co., Inc. (Employee, Shareholder)Merck & Co., Inc. (Employee, Shareholder) Joan R. Butterton, MD, Merck & Co., Inc. (Employee, Shareholder) Amanda Paschke, MD MSCE, Merck & Co., Inc. (Employee, Shareholder) Luke F. Chen, MBBS MPH MBA FRACP FSHEA FIDSA, Merck & Co., Inc. (Employee, Shareholder)Merck & Co., Inc. (Employee, Shareholder)