Lean in healthcare: the unfilled promise?

In an effort to improve operational efficiency, healthcare services around the world have adopted process improvement methodologies from the manufacturing sector, such as Lean Production. In this paper we report on four multi-level case studies of the implementation of Lean in the English NHS. Our results show that this generally involves the application of specific Lean 'tools', such as 'kaizen blitz' and 'rapid improvement events', which tend to produce small-scale and localised productivity gains. Although this suggests that Lean might not currently deliver the efficiency improvements desired in policy, the evolution of Lean in the manufacturing sector also reveals this initial focus on the 'tool level'. In moving to a more system-wide approach, however, we identify significant contextual differences between healthcare and manufacturing that result in two critical breaches of the assumptions behind Lean. First, the customer and commissioner in the private sector are the one and the same, which is essential in determining 'customer value' that drives process improvement activities. Second, healthcare is predominantly designed to be capacity-led, and hence there is limited ability to influence demand or make full use of freed-up resources. What is different about this research is that these breaches can be regarded as not being primarily 'professional' in origin but actually more 'organisational' and 'managerial' and, if not addressed could severely constrain Lean's impact on healthcare productivity at the systems level. © 2011 Elsevier Ltd

Synergistic targeting of BRCA1 mutated breast cancers with PARP and CDK2 inhibition

Abstract Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly to targeted therapies and chemotherapies. In order to define therapeutically targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, and define therapeutic subsets. We tested the same hypothesis for BLBC. Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between BRCA1 loss and high cyclin E1 protein expression, in contrast to HGSOC in which CCNE1 amplification drives increased cyclin E1. In cell lines, BRCA1 loss was associated with stabilized cyclin E1 during the cell cycle, and BRCA1 siRNA led to increased cyclin E1 in association with reduced phospho-cyclin E1 T62. Mutation of cyclin E1 T62 to alanine increased cyclin E1 stability. We showed that tumors with high cyclin E1/BRCA1 mutation in the BLBC cohort also had decreased phospho-T62, supporting this hypothesis. Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized with PARP inhibitors to reduce cell viability in cell lines with homologous recombination deficiency, including BRCA1 mutated cell lines. Treatment of BRCA1 mutant BLBC patient-derived xenograft models with combination PARP and CDK2 inhibition led to tumor regression and increased survival. We conclude that BRCA1 status and high cyclin E1 have potential as predictive biomarkers to dictate the therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC

The Long and Winding Road: An Independent Evaluation of the Implementation and Adoption of the National Health Service Care Records Service (NHS CRS) in Secondary Care in England

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Quasi-weekly, year-round oceanographic and ice measurements at the coastal Western Antarctic Peninsula from 1997 to 2018

CTD: until 2003, a Chelsea Instruments Aquapak was used, with sampling to 200m due to the depth rating. Since then an SBE19 and SBE19+ have been alternated between use on station and servicing in the UK. These have been calibrated during servicing and compared with an SBE911+ CTD on board R/V Laurence M. Gould on joint casts (SBE19 tied to frame) and samples analysed on a Guildline Autosal 8400B Laboratory Salinometer Ammonium: samples were measured on a Turner TD-700 fluorometer. Macronutrients: from 1998 to 2017, samples were analysed on QuAAtro39 segmented flow auto-analyser at NOCS https://www.southampton.ac.uk/oes/research/facilities/dissolved-inorganic-and-organic-nutrient.page . From 2017 to 2018, samples were analysed on a SEAL analytical AAIII segmented flow colorimetric auto-analyser (Woodward and Rees, 2001). Chlorophyll: samples were measured on a Turner AU-10 fluorometer. Oxygen isotopes: From 1998 to 2012, the delta-O-18 measurements were made with a SIRA 10 mass spectrometer plus Isoprep18 device. From 2012 to 2017, the delta-O-18 measurements were made with an Isoprime 100 mass spectrometer plus Aquaprep device.,Year-round measurements of the water column in Ryder Bay, Western Antarctic Peninsula have been collected by the Rothera Marine Assistant and associated researchers, starting in 1997 as part of the Rothera Oceanographic and Biological Time Series (RATS) to assess temporal variability in physical and biogeochemical oceanographic properties. The data were collected using instrumentation deployed from rigid inflatable boats, or through instrumentation deployed through holes cut in the sea ice when the bay is frozen over in winter. Data collected include profiles to about 500m depth with a conductivity-temperature-depth (CTD) system that produces measurements of temperature, salinity, fluorescence and photosynthetically-active radiation (PAR). Individual water samples are collected with a Niskin bottle from a standard 15m depth, with some samples also collected from the surface layer. These individual samples are analysed for size-fractionated chlorophyll, macronutrients (nitrate, nitrite, ammonium, orthophosphate and silicic acid), stable isotopes of oxygen in seawater, and some ancillary parameters. The bottle data have been quality controlled using international reference standards. Profiling and water sample collection occur with quasi-weekly frequency in summer and weekly in winter, but are weather and sea ice dependent. In addition, daily assessments of sea ice concentration and sea ice type are made from nearby Rothera Research Station by visual inspection, to aid interpretation of the ocean data collected. These data constitute one of the longest time series of ocean measurements in Antarctica, with near-unique systematic data collection in winter, within either polar circle. Data collection has been supported since 1997 by the Natural Environment Research Council (NERC) through core funding supplied to the British Antarctic Survey. Since 2017, it has been supported by NERC award &ldquo;National Capability - Polar Expertise Supporting UK Research&ldquo; (NE/R016038/1).,Profile instrumentation was collected with a self-logging conductivity-temperature-depth (CTD) profiler, deployed from a rigid inflatable boat (RIBs) or sea ice sled and lowered on a hand-turned winch using a Kevlar rope. RIBs departed/returned to nearby Rothera Research Station. During periods of fast-ice cover in winter, profiling was conducted through holes cut in the ice. Three sites were targeted - a primary site (in approximately 500m water depth), a secondary site, and a tertiary site (very close to Rothera). When the primary site was unreachable due to sea ice, the secondary site was occupied, and failing that an approximately 100m cast was carried out somewhere accessible. When weather or ice were prohibitive, no data/samples were collected and there is also a gap due to the CTD being lost to a fire in winter 2001. Data are downloaded upon return to Rothera Research Station. Water samples were collected with a Niskin bottle, closed with a messenger, and either processed in the laboratories at Rothera or stored for shipping back to the UK for analysis. Water samples for macronutrients were filtered and frozen at -20 &deg;C other than Ammonium, which is measured locally. Ammonium: NH4 was measured at Rothera Research Station typically within four hours of collection. From 1997 to 2005 ammonium measurements were carried out using the indophenol technique adapted to utilise dichloroisocyanurate as the chlorine donor and a modified UV incubation (Catalano, 1987). The measurements were calibrated by spiking of triplicate samples with 0.25 to 2.5 &micro;M NH4Cl (Clarke and Leakey, 1996). From 2005, ammonium measurements were carried out using ortho-phthaldialdehyde (OPA) and fluorometry (Holmes et al., 1999). Sample measurements were carried out in triplicate, and calibrated using standard addition comprising four concentrations, also in triplicate (Clarke et al., 2008). Other macronutrients: Nitrate (NO3), nitrite (NO2), orthophosphate (PO4) and silicic acid (Si(OH)4) were measured in the UK using a standard nutrient autoanalyser approach (Strickland and Parsons, 1968). From 1998 to 2017, the samples were measured at National Oceanography Centre, Southampton; from 2017 to 2018, the samples were measured at the Plymouth Marine Laboratory. Chlorophyll: Collected water samples were gently mixed by inversion, and triplicate samples (100 ml in summer and 500ml in winter) were filtered immediately on return to the research station by gravity through sequential 47 mm filters as follows: i) Microphytoplankton (&amp;gt;20 &micro;m nylon mesh), ii) Large nanophytoplankton (5 to 20 &micro;m membrane filter), iii) Small nanophytoplankton (2 to 5 &micro;m membrane filter) Picophytoplankton (0.2 to 2 &micro;m membrane filter). Pigments were extracted into chloroform/methanol (Wood, 1985) and measured by fluorometry before and after addition of two drops of 0.1N HCl under low light levels. Calibration is carried out twice a year using chlorophyll a standards, with samples diluted as required during strong phytoplankton blooms to reduce the range of values measured. The ratio of fluorescence before and after acidification is used to assess the reliability of the phaeopigement data. All data are reported as chlorophyll a (calculated as total chlorophyll minus phaeopigment; Clarke et al., 2008). Oxygen isotopes: Unfiltered samples were stored in capped and sealed glass bottles with rubber inserts and minimal head space, and stored in the dark at +4 &deg;C during transport to the UK (Meredith et al., 2008). The samples were measured for oxygen isotopes using the CO2 equilibration method for oxygen (Epstein and Mayeda, 1953) in triplicate (Natural Environment Research Council Isotope Geosciences Laboratory, Keyworth, UK).,Salinity (and therefore effectively Density) In polar waters, with temperatures below approximately 4 &deg;C, density profiles largely follow the shape of the salinity profile. This means that salinity checks can also include density profile checks and the dynamical unlikeliness of density overturns. There are a limited number of casts with significant density overturns. As these would make the profiles unstable (dense water above less dense water) then is almost all cases they can be ascribed to sensor problems. They can happen throughout a profile but are more common at the surface of bottom of the profile. They were filtered by looking for an overturn of &amp;gt;0.05 kg m3 and also by looking for unusually large deviations between different mixed layer depth calculations (including using the 10m depth as the reference value). Spikes are then identified and removed manually in salinity in the initial processing (rats_cnv2mat). This is usually between 1 and 7 metres of data, though some profiles are completely removed (including events 1495 and 1999), where pump problems make all data invalid. The precision of the salinity data is ensured by salinity samples being collected and by joint casts between the RATS CTD(s) and that on the R/V Laurence M Gould, with adjustments applied in initial processing. Temperature Temperature has little effect on density in the range encountered and is therefore free to vary both up and down with depth such that there is no way to ascribe a profile to be physically implausible. The temperature data has been very robust, with no suspicious profiles and very tight matches in all joint casts, it is therefore presented as recorded, except for profiles with pump profiles, where the temperature looks less wrong than salinity but the depth the data is recorded at could be significantly different to the depth the water actually was when it entered the CTD. PAR From 2017 there have been repeating problems with the PAR sensors, despite servicing and changing sensors. Some values at depth are easily filtered as impossible but other times the values are within bounds, but the shape of the profile is unlikely. There are standard sampling issues, caused by the shade of the boat, ice and clouds, that means light can increase rapidly with time and/or depth. This makes filtering the problem profiles harder, without removing data where the sensor is working well. Often the shape of the profile is more important than the absolute values so these profiles that increase with depth are of reduced value. The first filtering is to use a mask created from the first 700 events and also remove values </span

Air pollution and its effects on lichens, bryophytes, and lichen-feeding Lepidoptera: review and evidence from biological records

Changing air quality has been one of the most important drivers of change for bryophytes and lichens in Britain and Ireland over the 20th Century, with acidic pollutants such as sulphur dioxide having large effects on the ranges and abundances of many species. At the same time, expert amateur and professional naturalists have put enormous efforts into recording the distributions of species within these groups. These efforts have provided much evidence for declines and recoveries within the bryophytes and lichens, with species distribution data being linked to airborne pollutants in many different ways. We provide a broad overview of some of the changes that have occurred in affected species, using biological records collected by national recording schemes to illustrate the various effects of air pollution; we also review the direct and indirect impacts of air pollutants on these groups. Environmental change affecting one group of species is also likely to cascade to other groups where trophic or other relationships exist between them. Using data from the volunteer-based National Moth Recording Scheme, we provide the first evidence for an indirect association between reductions in air pollution and increases in lichenivorous moths