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In the framework of the ACCLIP project (Asian summer monsoon Chemical and CLimate Impacts project), a measurement campaign was conducted during summer 2022 in the Western Pacific region, to investigate the impact of the Asian Summer Monsoon (ASM) on the composition of the upper troposphere and lower stratosphere (UTLS). Fifteen research flights were carried out by the NASA WB-57 stratospheric aircraft and 14 by the NCAR/NSF GV, with base in Osan (South Korea), covering a large region on the eastern edge of the ASM anticyclone.We report on the Carbon Monoxide (CO) measurements performed by three different mid-infrared absorption spectrometers (COLD2, COMA and ACOS) installed onboard the WB-57 and by two different infrared absorption spectrometers (Aerodyne-CO and Picarro G2401) installed on the GV. Positive CO anomalies, never measured before in the UTLS outside direct biomass burning plumes, were collected by all sensors, showing a very good agreement. During the flight of the 19th of August, CO mixing ratio values higher than 250 ppb were registered at altitude around 14-15 km.A comparison with the CO observations measured by the instrument COLD2 during the StratoClim (Stratospheric and upper tropospheric processes for better Climate predictions) campaign, conducted in summer 2017 from Kathmandu (Nepal), will be presented. Particular attention will be paid to the CO difference observed in the UTLS, by sampling the anticyclone directly from the Tibetan Plateau during StratoClim campaign or from the Western Pacific during ACCLIP.

A series of in-situ Carbon Monoxide (CO) observations were recently performed in the Western Pacific region, during summer 2022, in the framework of the ACCLIP project (Asian summer monsoon Chemical and CLimate Impacts Project). During the ACCLIP measurements campaign, located in Osan (South Korea), two different research aircraft were employed with a set of sensors installed onboard. The NASA WB-57 aircraft carried out 15 research flights (reaching a maximum altitude of about 19 km), and the NSF/NCAR Gulfstream (GV) aircraft carried out 14 research flights (reaching a maximum altitude of about 15 km), covering a large region near Korea and Japan.We report on the inter-comparison between five different instruments for in-situ CO mixing ratio measurements: three installed onboard WB-57 (ACOS, COLD2 and COMA), and two installed onboard GV (Aerodyne-CO and Picarro G2401-m). COLD2 (Carbon Oxide Laser Detector 2) [1] and Aerodyne-CO [2] are mid-infrared Quantum Cascade Laser spectrometers, based on direct absorption in combination with a multipass cell. ACOS (Carbonyl Sulfide Analyzer) [3] and COMA (Carbon mOnoxide Measurement from Ames) [4] are mid-infrared absorption spectrometers based on Off-Axis ICOS (Integrated Cavity Output Spectroscopy) technology. The Picarro sensor is a cavity ring down absorption spectrometer [5].The in-flight CO mixing ratio values measured by the five spectrometers will be compared, with particular attention to both the accuracy of each instrument and the adopted or not-adopted calibration procedures, as, in principle, for many measurement environments the two sensors based on direct absorption do not need in-flight calibration. Laboratory measurements of common primary and secondary calibration standards made by the five CO measurement groups will be presented to increase confidence in method accuracy. [1] Viciani S., Montori A., Chiarugi A., and D’Amato F.: "A Portable Quantum Cascade Laser Spectrometer for Atmospheric Measurements of Carbon Monoxide", Sensors, 18, 2380 -1-18 (2018).[2] https://www.eol.ucar.edu/instruments/carbon-monoxide-co-and-nitrous-oxide-n%E2%82%82o-qcl-instrument[3] https://ams.confex.com/ams/103ANNUAL/meetingapp.cgi/Paper/421824[4] https://espo.nasa.gov/acclip/instrument/COMA[5] https://www.eol.ucar.edu/instruments/airborne-carbon-dioxide-co2-methane-ch4-carbon-monoxide-co-and-water-vapor-h2o

PURPOSE Despite extensive randomized evidence supporting the use of treatment breaks in metastatic colorectal cancer (mCRC), they are not universally offered to patients despite improvements in quality of life without detriment to overall survival (OS). FOCUS4-N was set up to explore the impact of oral maintenance therapy in patients who are responding to first-line therapy. METHODS FOCUS4 was a molecularly stratified trial program that registered patients with newly diagnosed mCRC. The FOCUS4-N trial was offered to patients in whom a targeted subtrial was unavailable or biomarker tests failed. Patients were randomly assigned using a 1:1 ratio between maintenance capecitabine and active monitoring (AM). The primary outcome was progression-free survival (PFS) with secondary outcomes including OS toxicity and tolerability. RESULTS Between March 2014 and March 2020, 254 patients were randomly assigned (127 to capecitabine and 127 to AM) across 88 UK sites. Baseline characteristics were balanced. There was strong evidence of efficacy for PFS (hazard ratio = 0.40; 95% CI, 0.21 to 0.75; P < .0001), but no significant improvement in OS (hazard ratio, 0.93; 95% CI, 0.69 to 1.27; P = .66) was observed. Compliance with treatment was good, and toxicity from capecitabine versus AM was as expected with grade ≥ 2 fatigue (25% v 12%), diarrhea (23% v 13%), and hand-foot syndrome (26% v 3%). Quality of life showed little difference between the groups. CONCLUSION Despite strong evidence of disease control with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as safe management alternatives for patients who are stable or responding to first-line treatment for mCRC. Capecitabine without bevacizumab may be used to extend PFS in the interval after 16 weeks of first-line therapy.

AimsFOCUS4 was a phase II/III umbrella trial, recruiting patients with advanced or metastatic colorectal cancer, between 2014 and 2020. Molecular profiling of patients’ formalin-fixed, paraffin-embedded tumour blocks was undertaken at two centralised biomarker laboratories (Leeds and Cardiff), and the results fed directly to the Medical Research Council Clinical Trials Unit, and used for subsequent randomisation. Here the laboratories discuss their experiences.MethodsFollowing successful tumour content assessment, blocks were sectioned for DNA extraction and immunohistochemistry (IHC). Pyrosequencing was initially used to determine tumour mutation status (KRAS, NRAS, BRAF and PIK3CA), then from 2018 onwards, next-generation sequencing was employed to allow the inclusion of TP53. Protein expression of MLH1, MSH2, MSH6, PMS2 and pTEN was determined by IHC. An interlaboratory comparison programme was initiated, allowing sample exchanges, to ensure continued assay robustness.Results1291 tumour samples were successfully analysed. Assay failure rates were very low; 1.9%–3.3% for DNA sequencing and 0.9%–1.3% for IHC. Concordance rates of >98% were seen for the interlaboratory comparisons, where a result was obtained by both laboratories.ConclusionsPractical and logistical problems were identified, including poor sample quality and difficulties with sample anonymisation. The often last-minute receipt of a sample for testing and a lack of integration with National Health Service mutation analysis services were challenging. The laboratories benefitted from both pretrial validations and interlaboratory comparisons, resulting in robust assay development and provided confidence during the implementation of new sequencing technologies. We conclude that our centralised approach to biomarker testing in FOCUS4 was effective and successful.

Outcomes inPatients with newly diagnosed mCRC were registered into FOCUS4 and tested forFOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) wereIn this phase II randomized trial, adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for

3504 Background: There is extensive randomised evidence supporting the use of treatment breaks in mCRC, but breaks from treatment are not universally offered to patients despite reductions in toxicity, without detriment to OS. Prior trials have shown that the combination of Cp and bevacizumab extend PFS but not OS. FOCUS4-N explores oral maintenance Cp monotherapy in patients with disease control on first line therapy. Methods: FOCUS4 was a molecularly stratified trial programme registering patients with newly diagnosed mCRC from 88 hospitals in the UK. Whilst undergoing 16 wks of first line treatment, a sample of tumour was sent for laboratory testing to stratify their disease into molecular subtypes: MSI, BRAF, PIK3CA, TP53 and RAS mutations. For some molecular groups, a targeted therapy subtrial was available but entry into the FOCUS4-N trial was offered to those in whom a targeted subtrial was unavailable. Patients were randomised 1:1 between maintenance Cp therapy or AM. The primary outcome was PFS assessed using 8-wkly RECIST reported CT scans with quality of life (using EQ5D 8 weekly) and OS as secondary outcomes. Toxicity and tolerability were assessed 4-wkly. On progression, from the nadir, patients recommenced first line treatment. Cox regression was used to assess efficacy by intention-to-treat (ITT) with adjustment for tumour location, WHO status, metastatic burden, first line treatment and biomarker subtype. Results: Between March 2014 and March 2020, 254 patients were randomised (127 to Cp and 127 to AM). Baseline characteristics were balanced between groups but event rates were higher than anticipated in the AM group and the final analysis was triggered early as a result of the COVID-19 pandemic halting recruitment. The table presents results for PFS and OS. Compliance with treatment was good with per-protocol analysis results very similar to ITT (PFS HR=0.38 (95% CI 0.28-0.51)). Toxicity from Cp v AM was as expected with G≥2 fatigue (25% v 12%), diarrhoea (23% v 13%) and hand-foot syndrome (26% v 3%). Quality of life showed no statistically significant differences between the two arms. Conclusions: Despite strong evidence of prolongation of PFS with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as a safe management alternative for patients who are stable or responding well to first line treatment for mCRC. Cp without bevacizumab may be used to extend PFS, in the interval after 16 weeks of combination therapy. Clinical trial information: ISRCTN#90061546. [Table: see text]

The Iron Age hill fort at Burrough Hill, Leicestershire, eastern England, lies in a lowland landscape of Mesozoic sedimentary rocks comprising mudstones with thin limestone units, sandstones and ironstones, which are blanketed by Pleistocene till. During the late Iron Age the hill fort was an important central place; permanent occupation probably began in Early–Middle Iron Age and continued into the Roman period. A variety of materials in archaeological contexts from the site, including clay rampart bonding and the clay linings of storage pits and floors, are found to yield characteristically mixed microfossil assemblages of Early to Late Jurassic ostracods and foraminifera, together with foraminifera from the Late Cretaceous. These provide a unique microfossil signature that indicate provenance from the local till. Microfossils can also be recovered from Middle to Late Iron Age potsherds at Burrough Hill, and these too suggest a local glacial source for the clay. Our analysis demonstrates the power of microfossils to provenance clay materials used for construction and manufactures at an Iron Age site, where a detailed baseline understanding of the local geology is firmly established.

The G2/M arrest function of human papillomavirus (HPV) E4 proteins is hypothesized to be necessary for viral genome amplification. Full-length HPV18 E1^E4 protein is essential for efficient viral genome amplification. Here we identify key determinants within a CDK-bipartite consensus recognition motif in HPV18 E1^E4 that are critical for association with active CDK–cyclin complexes and in vitro phosphorylation at the predicted CDK phosphorylation site (threonine 23). The optimal cyclin-binding sequence ( 43 RRLL 46 ) within this E4 motif is required for G2/M arrest of primary keratinocytes and correlates with cytoplasmic retention of cyclin B1, but not cyclin A. Disruption of this motif in the E4 ORF of HPV18 genomes, and the subsequent generation of stable cell lines in primary keratinocytes revealed that this motif was not essential for viral genome amplification or L1 capsid protein induction. We conclude that the HPV18 E4 G2/M arrest function does not play a role in early vegetative events.

Information regarding factors influencing prognosis and quality of life (QoL) in patients with amyotrophic lateral sclerosis (ALS) is useful for clinicians and also for patients and their carers. The aims of this study are to identify prognostic factors for survival in ALS and to determine the physical factors influencing QoL. This study is a retrospective analysis of a cohort of 512 patients who participated in a phase II/III clinical trial of olesoxime. Cox multivariate regression analysis found older age, bulbar onset disease, low baseline forced vital capacity, low baseline manual muscle test (MMT) scores and a shorter diagnostic delay to be independently associated with poor survival outcome. Physical factors shown to have the strongest correlation with poor QoL were low weight and a reduced ability to climb stairs. Therapeutic interventions including gastrostomy and non-invasive ventilation had no positive impact on QoL in this cohort. The prognostic factors for survival identified here are consistent with other studies of ALS patients, with the additional identification of baseline MMT score as another predictor of prognosis. Furthermore, the correlation between both weight and poor lower limb function with QoL is novel and underlines the importance of careful nutritional management in this hypercatabolic condition.

Mycobacterium abscessus is a rapidly growing environmental mycobacterium commonly found in soil and water which is often also associated with infections in humans, particularly of the lung. We report herein the draft genome sequence of M. abscessus strain 47J26.