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Background Lateral compression type1 (LC-1) fragility fractures are a common, painful injury in older adults resulting in reduced mobility. The incidence of these fractures is increasing with the growing older adult population. The current standard of care is non-surgical management; however, patients with this injury are at risk of long-term immobility and related complications. INFIX is a pelvic fixation device used in younger patients with high-energy fractures. The device is fitted via a percutaneous technique with no external pin sites and has good purchase even in osteoporotic bone. It therefore has the potential to be well tolerated in patients with LC-1 fragility fractures. INFIX could improve patients’ ability to mobilise and reduce the risk of immobility-related complications. However, there is a risk of complications related to surgery, and robust evidence is required on patient outcomes. This study will investigate the clinical and cost-effectiveness of surgical fixation with INFIX compared to non-surgical management of LC-1 fragility fractures in older adults. Methods A multi-centre randomised controlled trial of 600 patients allocated 1:1 to non-surgical management or INFIX surgery. The study will have a 12-month internal pilot to assess recruitment and trial feasibility. The primary outcome will be the patient quality of life over 6 months, measured by the patient-reported EQ-5D-5L. The secondary outcomes will include physical function, mental health, pain, delirium, imaging assessment, resource use, and complications. Discussion The L1FE study aims to compare the clinical and cost-effectiveness of surgical and non-surgical management of people aged 60 years and older with LC-1 fragility fractures. The trial is sufficiently powered and rigorously designed to inform future clinical and patient decision-making and allocation of NHS resources. Trial registration International Standard Randomised Controlled Trial Number Registry ISRCTN16478561. Registered on 8 April 2019

Background Acute leukaemias (AL) are life-threatening blood cancers that can be potentially cured with treatment involving myelosuppressive, multiagent, intensive chemotherapy (IC). However, such treatment is associated with a risk of serious infection, in particular invasive fungal infection (IFI) associated with prolonged neutropenia. Current practice guidelines recommend primary antifungal (AF) prophylaxis to be administered to high-risk patients to reduce IFI incidence. AFs are also used empirically to manage prolonged neutropenic fever. Current strategies lead to substantial overuse of AFs. Galactomannan (GM) and β-D-glucan (BG) biomarkers are also used to diagnose IFI. Combining both biomarkers may enhance the predictability of IFI compared to administering each test alone. Currently, no large-scale randomised controlled trial (RCT) has directly compared a biomarker-based diagnostic screening strategy without AF prophylaxis to AF prophylaxis (without systematic biomarker testing). Methods BioDriveAFS is a multicentre, parallel, two-arm RCT of 404 participants from UK NHS Haematology departments. Participants will be allocated on a 1:1 basis to receive either a biomarker-based antifungal stewardship (AFS) strategy, or a prophylactic AF strategy, which includes existing standard of care (SoC). The co-primary outcomes will be AF exposure in the 12-month post randomisation and the patient-reported EQ-5D-5L measured at 12-month post randomisation. Secondary outcomes will include total AF exposure, probable/proven IFI, survival (all-cause mortality and IFI mortality), IFI treatment outcome, AF-associated adverse effects/events/complications, resource use, episodes of neutropenic fever requiring hospital admission or outpatient management, AF resistance in fungi (non-invasive and invasive) and a Desirability of Outcome Ranking. The trial will have an internal pilot phase during the first 9 months. A mixed methods process evaluation will be integrated in parallel to the internal pilot phase and full trial, aiming to robustly assess how the intervention is delivered. Cost-effectiveness analysis will also be performed. Discussion The BioDriveAFS trial aims to further the knowledge of strategies that will safely optimise AF use through comparison of the clinical and cost-effectiveness of a biomarker-led diagnostic strategy versus prophylactic AF to prevent and manage IFI within acute leukaemia. The evidence generated from the study will help inform global clinical practice and approaches within antifungal stewardship. Trial registration ISRCTN11633399. Registered 24/06/2022.

The interplay between an evolving cancer and a dynamic immune microenvironment remains unclear. Here we analyse 258 regions from 88 early-stage, untreated non-small-cell lung cancers using RNA sequencing and histopathology-assessed tumour-infiltrating lymphocyte estimates. Immune infiltration varied both between and within tumours, with different mechanisms of neoantigen presentation dysfunction enriched in distinct immune microenvironments. Sparsely infiltrated tumours exhibited a waning of neoantigen editing during tumour evolution, indicative of historical immune editing, or copy-number loss of previously clonal neoantigens. Immune-infiltrated tumour regions exhibited ongoing immunoediting, with either loss of heterozygosity in human leukocyte antigens or depletion of expressed neoantigens. We identified promoter hypermethylation of genes that contain neoantigenic mutations as an epigenetic mechanism of immunoediting. Our results suggest that the immune microenvironment exerts a strong selection pressure in early-stage, untreated non-small-cell lung cancers that produces multiple routes to immune evasion, which are clinically relevant and forecast poor disease-free survival. RNA sequencing data and tumour pathology observations of non-small-cell lung cancers indicate that the immune cell microenvironment exerts strong evolutionary selection pressures that shape the immune-evasion capacity of tumours.

Background Lateral compression type1 (LC-1) fragility fractures are a common, painful injury in older adults resulting in reduced mobility. The incidence of these fractures is increasing with the growing older adult population. The current standard of care is non-surgical management; however, patients with this injury are at risk of long-term immobility and related complications. INFIX is a pelvic fixation device used in younger patients with high-energy fractures. The device is fitted via a percutaneous technique with no external pin sites and has good purchase even in osteoporotic bone. It therefore has the potential to be well tolerated in patients with LC-1 fragility fractures. INFIX could improve patients' ability to mobilise and reduce the risk of immobility-related complications. However, there is a risk of complications related to surgery, and robust evidence is required on patient outcomes. This study will investigate the clinical and cost-effectiveness of surgical fixation with INFIX compared to non-surgical management of LC-1 fragility fractures in older adults. Methods A multi-centre randomised controlled trial of 600 patients allocated 1:1 to non-surgical management or INFIX surgery. The study will have a 12-month internal pilot to assess recruitment and trial feasibility. The primary outcome will be the patient quality of life over 6 months, measured by the patient-reported EQ-5D-5L. The secondary outcomes will include physical function, mental health, pain, delirium, imaging assessment, resource use, and complications. Discussion The L1FE study aims to compare the clinical and cost-effectiveness of surgical and non-surgical management of people aged 60 years and older with LC-1 fragility fractures. The trial is sufficiently powered and rigorously designed to inform future clinical and patient decision-making and allocation of NHS resources. Trial registration International Standard Randomised Controlled Trial Number Registry ISRCTN16478561. Registered on 8 April 2019 Keywords: INFIX surgery, Lateral compression type 1, LC-1, Pelvic fracture fixation, Elderly patients, Older adults, Fragility fracture, Osteoporotic bone, Pubic ramus fracture, Immobility-related complications

The most common cause of death in children with chronic kidney disease (CKD) is cardiovascular disease. Abnormal mineral metabolism in CKD predisposes patients particularly those on dialysis, to vascular calcification which develops in the tunica media and is known as arteriosclerosis. Vascular calcification is a highly regulated, cell mediated process that predominantly involves vascular smooth muscle cells (VSMCs) which undergo apoptosis, depletion of calcification inhibitors and osteochondrocytic differentiation. CKD patients are often deficient in vitamin D which is activated in the kidney by 1α hydroxylase. These patients are routinely prescribed vitamin D receptor activators (VDRAs) in order to prevent secondary hyperparathyroidism and bone mineral disorders. Vitamin D has a bimodal effect on vascular calcification with both low and high levels associated with increased risk of calcification. Current literature on VDRA effects on VSMC calcification in vitro is conflicting with some increasing calcification and others having a protective effect. It is important to understand the mechanisms of action of different VDRAs at both physiological and supra physiological doses. Therefore this study will use a clinically relevant model of intact vessel rings from predialysis CKD and dialysis CKD patients to compare the effects of physiological doses of VDRAs on calcification in pre dialysis and dialysis vessels and to explain the mechanisms of action of VDRAs on VSMCs. VDRAs, alfacalcidol (inactive form) x10–8M and to a greater extent calcitriol (active form) x10–8M increased calcification in CKD vessel rings; this was more pronounced in dialysis than pre dialysis vessels. In addition calcitriol, but not alfacalcidol up regulated alkaline phosphatase activity (an osteogenic marker) in dialysis vessels. This data suggests that these VDRAs increase calcification via different mechanisms. Next the concentration dependant effect of calcitriol (x10–9M, x10–8M and x10–7M) on both healthy and dialysis human VSMCs were tested. RT-PCR showed that calcitriol affected the expression of multiple genes in particular the expression of the vitamin D receptor and the inactivating 24 hydroxylase enzyme were up regulated. This response was far greater in dialysis than healthy VSMCs, the differential response to vitamin D of these cells may in part explain the difference in susceptibility to calcification of healthy and dialysis vessels.

Abstract BackgroundThe BioDriveAFS trial aims to investigate whether a biomarker-based antifungal stewardship strategy is superior to a prophylactic antifungal strategy, including existing standard of care, in reducing antifungal therapy use in patients with acute leukaemia, without impacting health-related quality of life at 12 months. The trial will be commencing in the UK in 2022 and aims to recruit 500 patients across 40 sites. We hypothesized that a biomarker-led monitoring approach would be non-inferior to the standard of care approach utilizing antifungal prophylaxis. Patients and methodsPatients diagnosed with acute leukaemia who are planned to have intensive chemotherapy will be randomly allocated to one of two arms. The biomarker arm will consist of twice-weekly galactomannan and β-d-glucan until the end of intensive chemotherapy; positive biomarker results, neutropenic fever non-responsive to broad-spectrum antibacterials, or clinical suspicion will lead to investigation for potential invasive fungal infection as per international guidelines. Patients with proven or probable invasive fungal infection (IFI), as per the consensus definitions, will receive therapeutic antifungals, whereas those with possible or no IFI will have antifungals withheld. The control arm consists of local standard-of-care antifungal prophylaxis, including mould-active, without regular biomarker monitoring. ResultsPrimary outcome measures are exposure to therapeutic antifungal therapy and patient quality of life at 12 months versus baseline. Secondary outcome measures include total antifungal exposure, adverse events and complications, proven and probable IFI and treatment outcome, overall survival, all-cause mortality and IFI-related mortality. Resource use to determine cost-effectiveness and antifungal resistance in fungi will also be measured. FundingThe trial is funded by the National Institute for Health Research Health Technological Assessment Programme (NIHR132674) and supported by BSAC.

This corrects the article DOI: 10.1038/nature22364.

Nature 545, 446–451 (2017); doi:10.1038/nature22364 For 6 of the 96 patients included in this Article (patients CRUK0014, CRUK0030, CRUK0048, CRUK0059, CRUK0096 and CRUK0097) incorrect tumour volumetric data and positron emission tomography (PET) tumour background ratio (TBR) data were analysed. This error occurred because of the incorrect assignment of patient identifiers during the anonymization mandated by the independent review board of pre-operative computed tomography (CT) scans belonging to these patients.