Genetic and immune landscape evolution in MMR-deficient colorectal cancer.

Mismatch repair-deficient (MMRd) colorectal cancers (CRCs) have high mutation burdens, which make these tumours immunogenic and many respond to immune checkpoint inhibitors. The MMRd hypermutator phenotype may also promote intratumour heterogeneity (ITH) and cancer evolution. We applied multiregion sequencing and CD8 and programmed death ligand 1 (PD-L1) immunostaining to systematically investigate ITH and how genetic and immune landscapes coevolve. All cases had high truncal mutation burdens. Despite pervasive ITH, driver aberrations showed a clear hierarchy. Those in WNT/ß-catenin, mitogen-activated protein kinase, and TGF-ß receptor family genes were almost always truncal. Immune evasion (IE) drivers, such as inactivation of genes involved in antigen presentation or IFN-γ signalling, were predominantly subclonal and showed parallel evolution. These IE drivers have been implicated in immune checkpoint inhibitor resistance or sensitivity. Clonality assessments are therefore important for the development of predictive immunotherapy biomarkers in MMRd CRCs. Phylogenetic analysis identified three distinct patterns of IE driver evolution: pan-tumour evolution, subclonal evolution, and evolutionary stasis. These, but neither mutation burdens nor heterogeneity metrics, significantly correlated with T-cell densities, which were used as a surrogate marker of tumour immunogenicity. Furthermore, this revealed that genetic and T-cell infiltrates coevolve in MMRd CRCs. Low T-cell densities in the subgroup without any known IE drivers may indicate an, as yet unknown, IE mechanism. PD-L1 was expressed in the tumour microenvironment in most samples and correlated with T-cell densities. However, PD-L1 expression in cancer cells was independent of T-cell densities but strongly associated with loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD-L1 expression by cancer cells and may contribute to a higher recurrence risk of MMRd CRCs with impaired CDX2 expression. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The onset of star formation 250 million years after the Big Bang.

A fundamental quest of modern astronomy is to locate the earliest galaxies and study how they influenced the intergalactic medium a few hundred million years after the Big Bang1-3. The abundance of star-forming galaxies is known to decline4,5 from redshifts of about 6 to 10, but a key question is the extent of star formation at even earlier times, corresponding to the period when the first galaxies might have emerged. Here we report spectroscopic observations of MACS1149-JD1 6 , a gravitationally lensed galaxy observed when the Universe was less than four per cent of its present age. We detect an emission line of doubly ionized oxygen at a redshift of 9.1096 ± 0.0006, with an uncertainty of one standard deviation. This precisely determined redshift indicates that the red rest-frame optical colour arises from a dominant stellar component that formed about 250 million years after the Big Bang, corresponding to a redshift of about 15. Our results indicate that it may be possible to detect such early episodes of star formation in similar galaxies with future telescopes.

Randomized controlled trial of EndoRings assisted colonoscopy versus standard colonoscopy.

OBJECTIVES: The EndoRings device is a distal attachment consisting of two layers of circular flexible rings that evert mucosal folds. The aim of this study was to investigate whether EndoRing assisted colonoscopy (ER) improves polyp and adenoma detection compared to standard colonoscopy (SC). METHODS: Multicenter, parallel group, randomized controlled trial. RESULTS: Total of 556 patients randomized to ER (n = 275) or SC (n = 281). Colonoscopy completed in 532/556 (96%) cases. EndoRings removed in 74/275 (27%) patients. Total number of polyps in ER limb 582 vs. 515 in SC limb, P = 0.04. Total number of adenomas in ER limb 361 vs. 343 for SC limb, P = 0.49. A statistically significant difference in the mean number of polyps per patient in both the intention to treat (1.84 SC vs. 2.10 ER, P = 0.027) and per protocol (PP) (1.84 SC vs. 2.25 ER, P = 0.004). CONCLUSIONS: Our study shows promise for the EndoRings device to improve polyp detection.

Costimulation Blockade Disrupts CD4+ T Cell Memory Pathways and Uncouples Their Link to Decline in ß-Cell Function in Type 1 Diabetes.

We previously reported that costimulation blockade by abatacept limits the decline of ß-cell function and the frequency of circulating CD4+ central memory T cells (TCM) (CD45RO+CD62L+) in new-onset type 1 diabetes. In human subjects receiving placebo, we found a significant association between an increase in CD4+ TCM cells and the decline of ß-cell function. To extend and refine these findings, we examined changes in human CD4+ and CD8+ naive and memory T cell subsets at greater resolution using polychromatic flow and mass cytometry. In the placebo group, we successfully reproduced the original finding of a significant association between TCM and ß-cell function and extended this to other T cell subsets. Furthermore, we show that abatacept treatment significantly alters the frequencies of a majority of CD4+ conventional and regulatory T cell subsets; in general, Ag-naive subsets increase and Ag-experienced subsets decrease, whereas CD8+ T cell subsets are relatively resistant to drug effects, indicating a lesser reliance on CD28-mediated costimulation. Importantly, abatacept uncouples the relationship between changes in T cell subsets and ß-cell function that is a component of the natural history of the disease. Although these data suggest immunological markers for predicting change in ß-cell function in type 1 diabetes, the finding that abatacept blunts this relationship renders the biomarkers nonpredictive for this type of therapy. In sum, our findings point to a novel mechanism of action for this successful immunotherapy that may guide other disease-modifying approaches for type 1 diabetes.

Associations Between Gluteus Medius Trigger Points With Hip Passive Range of Movement and Muscle Strength in Adults With Chronic Nonspecific Low Back Pain: A Cross-Sectional Study.

OBJECTIVE: The purpose of this study was to investigate whether there is a relationship between gluteus medius trigger points with hip passive range of motion and hip muscle strength in people with chronic nonspecific low back pain (LBP). METHODS: This was a cross-sectional, blinded study that took place in 2 rural communities in New Zealand. Assessments were carried out in physiotherapy clinics in these towns. A total of 42 participants over 18 years old experiencing chronic nonspecific LBP were recruited. After meeting inclusion criteria, participants completed the following 3 questionnaires: Numerical Pain Rating Scale, Oswestry Disability Index, and Tampa Scale of Kinesiophobia. The primary researcher (a physiotherapist) assessed each participant's bilateral hip passive range of movement (using an inclinometer) and muscle strength (using a dynamometer). Following this, a blinded trigger point assessor examined the gluteus medius muscles for the presence of active and latent trigger points. RESULTS: General linear modeling using univariate analysis revealed that there was a positive association between hip strength and trigger point status (P =.03 left internal rotation, P =.04 right internal rotation, and P =.02 right abduction). Participants with no trigger points showed higher strength values (eg, right internal rotation standard error: 0.64), and those with trigger points showed lower strength. Overall, muscles exhibiting latent trigger points were the weakest (eg, right internal rotation standard error: 0.67). CONCLUSION: The presence of active or latent gluteus medius trigger points was associated with hip weakness in adults with chronic nonspecific LBP. There was no association between gluteus medius trigger points and hip passive range of movement.

A Gel Pad Designed to Measure Muscle Volume Using Freehand 3-Dimensional Ultrasonography.

We developed an innovative gel pad that covers the entire lower leg to remove artifacts due to the pressure of the transducer in freehand 3-dimensional ultrasonography. In comparison to the reference method in water, this study showed that this new method was valid (bias, 3.4 mL; limit of agreement, 7.7 mL for a volume of ≈220 mL) and reliable (coefficient of variation, <1.1%) for the measurement of gastrocnemius medialis muscle volume. Considering that it is easier to use than the water tank technique, it has much promise for volumetric measurement of many muscles.

Temporal patterns of seed germination in early spring-flowering temperate woodland geophytes are modified by warming.

BACKGROUND AND AIMS: Understorey species in temperate deciduous woodlands such as wild daffodil (Narcissus pseudonarcissus) and common snowdrop (Galanthus nivalis) have complex dormancy: seeds that are shed in late spring require warm summer temperatures for embryo elongation and dormancy alleviation, but then cooler temperatures for germination in autumn. As seasons warm and tree canopies alter, how will different seasonal temperature sequences affect these complex dormancy responses? METHODS: The effect of different sequences of warmer (+5 °C), current or cooler (-5 °C) seasons (summer to spring) on seed germination patterns over seven successive seasons were investigated, with all sequences combined factorially to determine the consequences of differential seasonal temperature change for the temporal pattern of germination (and so seedling recruitment). KEY RESULTS: Little (<1 %, G. nivalis) or no (N. pseudonarcissus) seed germination occurred during the first summer in any treatment. Germination of N. pseudonarcissus in the first autumn was considerable and greatest at the average (15 °C) temperature, irrespective of the preceding summer temperature; germination was also substantial in winter after a warmer autumn. Germination in G. nivalis was greatest in the warmest first autumn and influenced by preceding summer temperature (average > warmer > cooler); the majority of seeds that germinated over the whole study did so during the two autumns but also in year 2's cooler summer after a warm spring. CONCLUSIONS: Warmer autumns and winters delay first autumn germination of N. pseudonarcissus to winter but advance it in G. nivalis; overall, warming will deplete the soil seed bank of these species, making annual seed influx increasingly important for recruitment and persistence. This study provides a comprehensive account of the effects of temperature changes in different seasons on seed germination in these early spring-flowering geophytes and consequently informs how these and other temperate woodland species with complex seed dormancy may respond to future climate change.

Investigating the effects of inter-annual weather variation (1968-2016) on the functional response of cereal grain yield to applied nitrogen, using data from the Rothamsted Long-Term Experiments.

The effect of weather on inter-annual variation in the crop yield response to nitrogen (N) fertilizer for winter wheat (Triticum aestivvum L.) and spring barley (Hordeum vulgare L.) was investigated using yield data from the Broadbalk Wheat and Hoosfield Spring Barley long-term experiments at Rothamsted Research. Grain yields of crops from 1968 to 2016 were modelled as a function of N rates using a linear-plus-exponential (LEXP) function. The extent to which inter-annual variation in the parameters of these responses was explained by variations in weather (monthly summarized temperatures and rainfall), and by changes in the cultivar grown, was assessed. The inter-annual variability in rainfall and underlying temperature influenced the crop N response and hence grain yields in both crops. Asymptotic yields in wheat were particularly sensitive to mean temperature in November, April and May, and to total rainfall in October, February and June. In spring barley asymptotic yields were sensitive to mean temperature in February and June, and to total rainfall in April to July inclusive and September. The method presented here explores the separation of agronomic and environmental (weather) influences on crop yield over time. Fitting N response curves across multiple treatments can support an informative analysis of the influence of weather variation on the yield variability. Whilst there are issues of the confounding and collinearity of explanatory variables within such models, and that other factors also influence yields over time, our study confirms the considerable impact of weather variables at certain times of the year. This emphasizes the importance of including weather temporal variation when evaluating the impacts of climate change on crops.

A randomized clinical trial comparing early active motion programs: Earlier hand function, TAM, and orthotic satisfaction with a relative motion extension program for zones V and VI extensor tendon repairs.

STUDY DESIGN: Randomized clinical trial with parallel groups. INTRODUCTION: Early active mobilization programs are used after zones V and VI extensor tendon repairs; two programs used are relative motion extension (RME) orthosis and controlled active motion (CAM). Although no comparative studies exist, use of the RME orthosis has been reported to support earlier hand function. PURPOSE OF THE STUDY: This randomized clinical trial investigated whether patients managed with an RME program would recover hand function earlier postoperatively than those managed with a CAM program. METHODS: Forty-two participants with zones V-VI extensor tendon repairs were randomized into either a CAM or RME program. The Sollerman Hand Function Test (SHFT) was the primary outcome measure of hand function. Days to return to work, QuickDASH (Disabilities of Arm, Shoulder and Hand) questionnaire, total active motion (TAM), grip strength, and patient satisfaction were the secondary measures of outcome. RESULTS: The RME group demonstrated better results at four weeks for the SHFT score (P = .0073; 95% CI: -10.9, -1.8), QuickDASH score (P = .05; 95% CI: -0.05, 19.5), and TAM (P = .008; 95% CI: -65.4, -10.6). Days to return to work were similar between groups (P = .77; 95% CI: -28.1, 36.1). RME participants were more satisfied with the orthosis (P < .0001; 95% CI: 3.5, 8.4). No tendon ruptures occurred. DISCUSSION: Participants managed using an RME program, and RME finger orthosis demonstrated significantly better early hand function, TAM, and orthosis satisfaction than those managed by the CAM program using a static wrist-hand-finger orthosis. This is likely due to the less restrictive design of the RME orthosis. CONCLUSIONS: The RME program supports safe earlier recovery of hand function and motion when compared to a CAM program following repair of zones V and VI extensor tendons.

Music and Medicine Come Together Over Pain in the Air Medical Transport Environment.

OBJECTIVE: This study aimed to determine if noise-canceling headphones (NCHs) with music supersedes pain reduction of other hearing protection for patients transported by Guardian Air Transport via rotor or fixed wing aircraft from 2017 to 2019. METHODS: We designed a randomized pilot study in which patients who received NCHs with or without music were compared with controls who received non-NCH hearing protection alone. Four hundred fifty-four adults 19 to 64 years of age and 36 pediatric patients 4 to 18 years old who received ≥ 1 dose of opioids were included. RESULTS: In the aggregate population, opioid use was reduced by 31% from 14.3 to 10.0 morphine milligram equivalent/h transport (P = .131) with music compared with controls. The mean total pain reduction in the aggregate population from -2.5 (standard deviation [SD] = 3.2) to -4.0 (SD = 2.9) was 1.6-fold more than controls compared with NCH and music (P = .008). This effect was most profound in the pediatric population where the mean total pain reduction with NCHs and music (-5.4, SD = 3.1) was 3.4-fold more than controls (-1.6, SD = 2.7, P = .021). CONCLUSIONS: Music may provide greater subjective pain relief when combined with NCHs in the air transport environment; further research is required.

Proficiency Testing of Virus Diagnostics Based on Bioinformatics Analysis of Simulated In Silico High-Throughput Sequencing Data Sets.

Quality management and independent assessment of high-throughput sequencing-based virus diagnostics have not yet been established as a mandatory approach for ensuring comparable results. The sensitivity and specificity of viral high-throughput sequence data analysis are highly affected by bioinformatics processing using publicly available and custom tools and databases and thus differ widely between individuals and institutions. Here we present the results of the COMPARE [Collaborative Management Platform for Detection and Analyses of (Re-)emerging and Foodborne Outbreaks in Europe] in silico virus proficiency test. An artificial, simulated in silico data set of Illumina HiSeq sequences was provided to 13 different European institutes for bioinformatics analysis to identify viral pathogens in high-throughput sequence data. Comparison of the participants' analyses shows that the use of different tools, programs, and databases for bioinformatics analyses can impact the correct identification of viral sequences from a simple data set. The identification of slightly mutated and highly divergent virus genomes has been shown to be most challenging. Furthermore, the interpretation of the results, together with a fictitious case report, by the participants showed that in addition to the bioinformatics analysis, the virological evaluation of the results can be important in clinical settings. External quality assessment and proficiency testing should become an important part of validating high-throughput sequencing-based virus diagnostics and could improve the harmonization, comparability, and reproducibility of results. There is a need for the establishment of international proficiency testing, like that established for conventional laboratory tests such as PCR, for bioinformatics pipelines and the interpretation of such results.

Confirming the Clinical Safety and Feasibility of a Bundled Methodology to Improve Cardiopulmonary Resuscitation Involving a Head-Up/Torso-Up Chest Compression Technique.

OBJECTIVES: Combined with devices that enhance venous return out of the brain and into the thorax, preclinical outcomes are improved significantly using a synergistic bundled approach involving mild elevation of the head and chest during cardiopulmonary resuscitation. The objective here was to confirm clinical safety/feasibility of this bundled approach including use of mechanical cardiopulmonary resuscitation provided at a head-up angle. DESIGN: Quarterly tracking of the frequency of successful resuscitation before, during, and after the clinical introduction of a bundled head-up/torso-up cardiopulmonary resuscitation strategy. SETTING: 9-1-1 response system for a culturally diverse, geographically expansive, populous jurisdiction. PATIENTS: All 2,322 consecutive out-of-hospital cardiac arrest cases (all presenting cardiac rhythms) were followed over 3.5 years (January 1, 2014, to June 30, 2017). INTERVENTIONS: In 2014, 9-1-1 crews used LUCAS (Physio-Control Corporation, Redmond, WA) mechanical cardiopulmonary resuscitation and impedance threshold devices for out-of-hospital cardiac arrest. After April 2015, they also 1) applied oxygen but deferred positive pressure ventilation several minutes, 2) solidified a pit-crew approach for rapid LUCAS placement, and 3) subsequently placed the patient in a reverse Trendelenburg position (~20°). MEASUREMENTS AND MAIN RESULTS: No problems were observed with head-up/torso-up positioning (n = 1,489), but resuscitation rates rose significantly during the transition period (April to June 2015) with an ensuing sustained doubling of those rates over the next 2 years (mean, 34.22%; range, 29.76-39.42%; n = 1,356 vs 17.87%; range, 14.81-20.13%, for 806 patients treated prior to the transition; p < 0.0001). Outcomes improved across all subgroups. Response intervals, clinical presentations and indications for attempting resuscitation remained unchanged. Resuscitation rates in 2015-2017 remained proportional to neurologically intact survival (~35-40%) wherever tracked. CONCLUSIONS: The head-up/torso-up cardiopulmonary resuscitation bundle was feasible and associated with an immediate, steady rise in resuscitation rates during implementation followed by a sustained doubling of the number of out-of-hospital cardiac arrest patients being resuscitated. These findings make a compelling case that this bundled technique will improve out-of-hospital cardiac arrest outcomes significantly in other clinical evaluations.

Weakly haemolytic variants of Brachyspira hyodysenteriae newly emerged in Europe belong to a distinct subclade with unique genetic properties.

Brachyspira (B.) hyodysenteriae is widespread globally, and can cause mucohaemorrhagic colitis (swine dysentery, SD) with severe economic impact in infected herds. Typical strains of B. hyodysenteriae are strongly haemolytic on blood agar, and the haemolytic activity is believed to contribute to virulence in vivo. However, recently there have been reports of atypical weakly haemolytic isolates of B. hyodysenteriae (whBh). In this study, 34 European whBh and 82 strongly haemolytic isolates were subjected to comparative genomic analysis. A phylogenetic tree constructed using core single nucleotide polymorphisms showed that the whBh formed a distinct sub-clade. All eight genes previously associated with haemolysis in B. hyodysenteriae were present in the whBh. No consistent patterns of amino acid substitutions for all whBh were found in these genes. In contrast, a genome region containing six coding sequences (CDSs) had consistent nucleotide sequence differences between strongly and whBh isolates. Two CDSs were predicted to encode ABC transporter proteins, and a TolC family protein, which may have a role in the export of haemolysins from B. hyodysenteriae. Another difference in this region was the presence of three CDSs in whBh that are pseudogenes in strongly haemolytic isolates. One of the intact CDSs from whBh encoded a predicted PadR-like transcriptional repressor that may play a role in repression of haemolysis functions. In summary, a sub-clade of whBh isolates has emerged in Europe, and several genomic differences, that potentially explain the weakly haemolytic phenotype, were identified. These markers may provide targets for discriminatory molecular tests needed in SD surveillance.

Antibiotic treatment triggers gut dysbiosis and modulates metabolism in a chicken model of gastro-intestinal infection.

BACKGROUND: Infection of the digestive track by gastro-intestinal pathogens results in the development of symptoms ranging from mild diarrhea to more severe clinical signs such as dysentery, severe dehydration and potentially death. Although, antibiotics are efficient to tackle infections, they also trigger dysbiosis that has been suggested to result in variation in weight gain in animal production systems. RESULTS: Here is the first study demonstrating the metabolic impact of infection by a gastro-intestinal pathogen (Brachyspira pilosicoli) and its resolution by antibiotic treatment (tiamulin) on the host (chicken) systemic metabolism and gut microbiota composition using high-resolution 1H nuclear magnetic resonance (NMR) spectroscopy and 16S rDNA next generation sequencing (NGS). Clear systemic metabolic markers of infections such as glycerol and betaine were identified. Weight loss in untreated animals was in part explained by the observation of a modification of systemic host energy metabolism characterized by the utilization of glycerol as a glucose precursor. However, antibiotic treatment triggered an increased VLDL/HDL ratio in plasma that may contribute to reducing weight loss observed in treated birds. All metabolic responses co-occurred with significant shift of the microbiota upon infection or antibiotic treatment. CONCLUSION: This study indicates that infection and antibiotic treatment trigger dysbiosis that may impact host systemic energy metabolism and cause phenotypic and health modifications.

Imaging with ultrasound in physical therapy: What is the PT's scope of practice? A competency-based educational model and training recommendations.

Physical therapists employ ultrasound (US) imaging technology for a broad range of clinical and research purposes. Despite this, few physical therapy regulatory bodies guide the use of US imaging, and there are limited continuing education opportunities for physical therapists to become proficient in using US within their professional scope of practice. Here, we (i) outline the current status of US use by physical therapists; (ii) define and describe four broad categories of physical therapy US applications (ie, rehabilitation, diagnostic, intervention and research US); (iii) discuss how US use relates to the scope of high value physical therapy practice and (iv) propose a broad framework for a competency-based education model for training physical therapists in US. This paper only discusses US imaging-not 'therapeutic' US. Thus, 'imaging' is implicit anywhere the term 'ultrasound' is used.

Ultrasound assessment of extensor pollicis brevis tendon excursion in different wrist positions in healthy people.

STUDY DESIGN: Cross-sectional, observational study. INTRODUCTION: There is little reported on the in vivo mechanics and behavior of extensor pollicis brevis (EPB) in relation to wrist position. Wrist position is known to significantly influence tendon excursion and therefore function of the digits. Ultrasound imaging (USI) can be used to assess in vivo tendon behavior and excursion. An improved knowledge of the excursion of the EPB tendon is important in understanding normal tendon mechanics and potentially pathological tendon disorders such as de Quervains tenosynovitis. PURPOSE OF THE STUDY: To assess the reliability of using USI to measure EPB tendon excursion and to quantify EPB tendon excursion in 3 wrist positions. METHODS: USI with speckle-tracking analysis were utilized to assess 49 normal EPB tendons (25 subjects). Tendon excursion was measured in wrist flexion (45°), wrist neutral and wrist extension (45°) on 2 different occasions. RESULTS: The within- and between-session reliability of using USI to quantify EPB tendon excursion was "excellent" and "high," respectively. Wrist position had a significant influence on EPB tendon excursion (P ≤ .05). EPB excursion in the neutral wrist position was statistically greater than the other 2 positions (P < .05). DISCUSSION: EPB tendon excursion has been shown to be dependent on the wrist positions of flexion and extension. The measures are notably lower than those found in cadaver studies; however, they follow a similar pattern with greatest excursion occurring in the neutral wrist position and least in flexion. This information is useful for EPB tendon rehabilitation and in consideration of biomechanics and pathogenesis of disorders that affect EPB tendon. CONCLUSION: In vivo EPB tendon excursion measures have been quantified, and wrist position has been found to have an influence on excursion. USI with speckle-tracking analysis are considered to be reliable methods for measuring EPB tendon excursion.

Clinicopathological case: rapid cognitive decline and myoclonus associated with fever, arthropathy and scleritis.

A 65-year-old man presented with transient neurological symptoms, followed by rapid cognitive decline, myoclonus and fevers. He had evidence of scleritis and an arthropathy. This paper reports the clinicopathological conference discussed at the Association of British Neurologists Annual Meeting 2017.

3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial.

BACKGROUND: 6 months of oxaliplatin-containing chemotherapy is usually given as adjuvant treatment for stage 3 colorectal cancer. We investigated whether 3 months of oxaliplatin-containing chemotherapy would be non-inferior to the usual 6 months of treatment. METHODS: The SCOT study was an international, randomised, phase 3, non-inferiority trial done at 244 centres. Patients aged 18 years or older with high-risk stage II and stage III colorectal cancer underwent central randomisation with minimisation for centre, choice of regimen, sex, disease site, N stage, T stage, and the starting dose of capecitabine. Patients were assigned (1:1) to receive 3 months or 6 months of adjuvant oxaliplatin-containing chemotherapy. The chemotherapy regimens could consist of CAPOX (capecitabine and oxaliplatin) or FOLFOX (bolus and infused fluorouracil with oxaliplatin). The regimen was selected before randomisation in accordance with choices of the patient and treating physician. The primary study endpoint was disease-free survival and the non-inferiority margin was a hazard ratio of 1·13. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who started study treatment. This trial is registered with ISRCTN, number ISRCTN59757862, and follow-up is continuing. FINDINGS: 6088 patients underwent randomisation between March 27, 2008, and Nov 29, 2013. The intended treatment was FOLFOX in 1981 patients and CAPOX in 4107 patients. 3044 patients were assigned to 3 month group and 3044 were assigned to 6 month group. Nine patients in the 3 month group and 14 patients in the 6 month group did not consent for their data to be used, leaving 3035 patients in the 3 month group and 3030 patients in the 6 month group for the intention-to-treat analyses. At the cutoff date for analysis, there had been 1482 disease-free survival events, with 740 in the 3 month group and 742 in the 6 month group. 3 year disease-free survival was 76·7% (95% CI 75·1-78·2) for the 3 month group and 77·1% (75·6-78·6) for the 6 month group, giving a hazard ratio of 1·006 (0·909-1·114, test for non-inferiority p=0·012), significantly below the non-inferiority margin. Peripheral neuropathy of grade 2 or worse was more common in the 6 month group (237 [58%] of 409 patients for the subset with safety data) than in the 3 month group (103 [25%] of 420) and was long-lasting and associated with worse quality of life. 1098 serious adverse events were reported (492 reports in the 3 month group and 606 reports in the 6 month group) and 32 treatment-related deaths occurred (16 in each group). INTERPRETATION: In the whole study population, 3 months of oxaliplatin-containing adjuvant chemotherapy was non-inferior to 6 months of the same therapy for patients with high-risk stage II and stage III colorectal cancer and was associated with reduced toxicity and improved quality of life. Despite the fact the study was underpowered, these data suggest that a shorter duration leads to similar survival outcomes with better quality of life and thus might represent a new standard of care. FUNDING: Medical Research Council, Swedish Cancer Society, NETSCC, and Cancer Research UK.

SCOT: a comparison of cost-effectiveness from a large randomised phase III trial of two durations of adjuvant Oxaliplatin combination chemotherapy for colorectal cancer.

BACKGROUND: The Short Course Oncology Therapy (SCOT) study is an international, multicentre, non-inferiority randomised controlled trial assessing the efficacy, toxicity, and cost-effectiveness of 3 months (3 M) versus the usually given 6 months (6 M) of adjuvant chemotherapy in colorectal cancer. METHODS: In total, 6088 patients with fully resected high-risk stage II or stage III colorectal cancer were randomised and followed up for 3-8 years. The within-trial cost-effectiveness analysis from a UK health-care perspective is presented using the resource use data, quality of life (EQ-5D-3L), time on treatment (ToT), disease-free survival after treatment (DFS) and overall survival (OS) data. Quality-adjusted partitioned survival analysis and Kaplan-Meier Sample Average Estimator estimated QALYs and costs. Probabilistic sensitivity and subgroup analysis was undertaken. RESULTS: The 3 M arm is less costly (-£4881; 95% CI: -£6269; -£3492) and entails (non-significant) QALY gains (0.08; 95% CI: -0.086; 0.230) due to a better significant quality of life. The net monetary benefit was significantly higher in 3 M under a wide range of monetary values of a QALY. The subgroup analysis found similar results for patients in the CAPOX regimen. However, for the FOLFOX regimen, 3 M had lower QALYs than 6 M (not statistically significant). CONCLUSIONS: Overall, 3 M dominates 6 M with no significant detrimental impact on QALYs. The results provide the economic case that a 3 M treatment strategy should be considered a new standard of care.

Deep phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment.

Idiopathic aplastic anemia (AA) is an immune-mediated and serious form of bone marrow failure. Akin to other autoimmune diseases, we have previously shown that in AA regulatory T cells (Tregs) are reduced in number and function. The aim of this study was to further characterize Treg subpopulations in AA and investigate the potential correlation between specific Treg subsets and response to immunosuppressive therapy (IST) as well as their in vitro expandability for potential clinical use. Using mass cytometry and an unbiased multidimensional analytical approach, we identified 2 specific human Treg subpopulations (Treg A and Treg B) with distinct phenotypes, gene expression, expandability, and function. Treg B predominates in IST responder patients, has a memory/activated phenotype (with higher expression of CD95, CCR4, and CD45RO within FOXP3(hi), CD127(lo) Tregs), expresses the interleukin-2 (IL-2)/STAT5 pathway and cell-cycle commitment genes. Furthermore, in vitro-expanded Tregs become functional and take on the characteristics of Treg B. Collectively, this study identifies human Treg subpopulations that can be used as predictive biomarkers for response to IST in AA and potentially other autoimmune diseases. We also show that Tregs from AA patients are IL-2-sensitive and expandable in vitro, suggesting novel therapeutic approaches such as low-dose IL-2 therapy and/or expanded autologous Tregs and meriting further exploration.