•Primary school children often mirror-write left facing letters (such as J and Z).•This is also true for completely novel, artificial letter-like characters.•Children are three times more likely to ...mirror-write a left-facing character.•This is the first experimental evidence for a character-facing bias in development.•Children may extract general regularities of letter shape by statistical learning.
When learning to write, children often mirror-reverse individual letters. For children learning to use the Latin alphabet, in a left-to-right writing culture, letters that appear to face left (such as J and Z) seem to be more prone to reversal than those that appear to face right (such as B and C). It has been proposed that, because most asymmetrical Latin letters face right, children statistically learn this general regularity and are subsequently biased to write any letter rightward. The evidence for this character-facing bias is circumstantial, however, because letter-facing direction is confounded with other factors that could affect error rates; for instance, J and Z are left-facing, but they are also infrequent. We report the first controlled experimental test of the character-facing bias. We taught 43 Scottish primary schoolchildren (aged 4.8–5.8 years) four artificial, letter-like characters, two of which were left-facing and two of which were right-facing. The characters were novel and so were not subject to prior exposure effects, and alternate groups of children were assigned to identical but mirror-reflected character sets. Children were three times more likely to mirror-write a novel character they had learned in a left-facing format than to mirror-write one they had learned in a right-facing format. This provides the first experimental confirmation of the character-facing bias in literacy development and suggests that implicit knowledge acquired from exposure to written language is readily generalized to novel letter-like forms.
Sprat, Sprattus sprattus, is the dominant pelagic species in British inshore and estuarine waters. Within the Bristol Channel the population is almost totally composed of fish <3years old with the ...adults overwintering in Bridgwater Bay. Sprat follow regular seasonal migrations and occasionally form huge aggregations which together generate considerable between sample variability. Using a 36-year monthly time series collected in the Bristol Channel since 1980, together with two periods of intensive daily and weekly sampling, sprat growth is shown to have declined almost linearly over the last 36years coincident with increasing late summer-autumn seawater temperatures. Longevity has also declined, with age 3+ sprat >140mm standard length lost to the population by 1999. Further, adult condition, measured as the average weight of a 103mm standard length adult, declined rapidly from 13.7g in 2007 to 9g in 2011. Despite these changes, which would have reduced age-specific fecundity, a sign-rank test showed abundance of adult sprat has shown no long-term trend and Bulmer's test indicates density-dependent regulation is operating. While sprat recruitment is shown to be responding to the sunspot cycle, the North Atlantic Oscillation and sea water temperature, the impact of these variables on adult population density is damped because of density-dependent regulation. The result is that sprat respond to environmental change with large changes in their growth and condition, but the adult abundance is constrained and shows no long-term trend. Recruitment was modelled by combining a Ricker curve with terms for the response of sprat to solar activity, the North Atlantic Oscillation and spring temperature. It is shown that the stock-recruitment relationship does not form a simple curve, but is bounded within a region in which the upper and lower constraints are defined by environmental conditions. Within this bounded region the population trajectory under differing environmental regimes can be predicted.
•Sprat, Sprattus sprattus, is the dominant pelagic species within the Bristol Channel.•Using a 36-year monthly time series sprat growth is shown to have declined almost linearly over the last 36 years.•Longevity has declined, with large age 3+ sprat > 140 mm standard length lost to the population by 1999.•Adult condition, has shown a rapid decline from 13.7 g in 2007 to 9 g in 2011.•Bulmer’s test indicates density-dependent regulation is operating.•Sprat recruitment is responding to the sunspot cycle, the North Atlantic Oscillation and sea water temperature.
IntroductionMultiple myeloma is a bone marrow cancer, which predominantly affects older people. The incidence is increasing in an ageing population.Over the last 10 years, patient outcomes have ...improved. However, this is less apparent in older, less fit patients, who are ineligible for stem cell transplant. Research is required in this patient group, taking into account frailty and aiming to improve: treatment tolerability, clinical outcomes and quality of life.Methods and analysisFrailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma is a national, phase III, multicentre, randomised controlled trial comparing standard (reactive) and frailty-adjusted (adaptive) induction therapy delivery with ixazomib, lenalidomide and dexamethasone (IRD), and to compare maintenance lenalidomide to lenalidomide+ixazomib, in patients with newly diagnosed multiple myeloma not suitable for stem cell transplant. Overall, 740 participants will be registered into the trial to allow 720 and 478 to be randomised at induction and maintenance, respectively.All participants will receive IRD induction with the dosing strategy randomised (1:1) at trial entry. Patients randomised to the standard, reactive arm will commence at the full dose followed by toxicity dependent reactive modifications. Patients randomised to the adaptive arm will commence at a dose level determined by their International Myeloma Working Group frailty score. Following 12 cycles of induction treatment, participants alive and progression free will undergo a second (double-blind) randomisation on a 1:1 basis to maintenance treatment with lenalidomide+placebo versus lenalidomide+ixazomib until disease progression or intolerance.Ethics and disseminationEthical approval has been obtained from the North East—Tyne & Wear South Research Ethics Committee (19/NE/0125) and capacity and capability confirmed by local research and development departments for each participating centre prior to opening to recruitment. Participants are required to provide written informed consent prior to trial registration. Trial results will be disseminated by conference presentations and peer-reviewed publications.Trial registration numberISRCTN17973108, NCT03720041.
Minimal residual disease (MRD) can predict outcomes in patients with multiple myeloma, but limited data are available on the prognostic impact of MRD when assessed at serial time points in the ...context of maintenance therapy after autologous stem-cell transplant (ASCT) and the interaction between MRD and molecular risk.
Data from a large phase III trial (Myeloma XI) were examined to determine the relationship between MRD status, progression-free survival (PFS), and overall survival (OS) in post-ASCT patients randomly assigned to lenalidomide maintenance or no maintenance at 3 months after ASCT. MRD status was assessed by flow cytometry (median sensitivity 0.004%) before maintenance random assignment (ASCT + 3) and 6 months later (ASCT + 9).
At ASCT + 3, 475 of 750 (63.3%) patients were MRD-negative and 275 (36.7%) were MRD-positive. MRD-negative status was associated with improved PFS (hazard ratio HR = 0.47; 95% CI, 0.37 to 0.58
< .001) and OS (HR = 0.59; 95% CI, 0.40 to 0.85;
= .0046). At ASCT + 9, 214 of 326 (65.6%) were MRD-negative and 112 (34.4%) were MRD-positive. MRD-negative status was associated with improved PFS (HR = 0.20; 95% CI, 0.13 to 0.31;
< .0001) and OS (HR = 0.33; 95% CI, 0.15 to 0.75;
= .0077). The findings were very similar when restricted to patients with complete response/near complete response. Sustained MRD negativity from ASCT + 3 to ASCT + 9 or the conversion to MRD negativity by ASCT + 9 was associated with the longest PFS/OS. Patients randomly assigned to lenalidomide maintenance were more likely to convert from being MRD-positive before maintenance random assignment to MRD-negative 6 months later (lenalidomide 30%, observation 17%). High-risk molecular features had an adverse effect on PFS and OS even for those patients achieving MRD-negative status. On multivariable analysis of MRD status, maintenance therapy and molecular risk maintained prognostic impact at both ASCT + 3 and ASCT + 9.
In patients with multiple myeloma, MRD status at both ASCT + 3 and ASCT + 9 is a powerful predictor of PFS and OS.
Recent research has identified the existence of a freshwater reservoir effect influencing the radiocarbon dating of human skeletal remains from the Dnieper region of Ukraine (Lillie et al. 2009). The ...current study outlines the evidence for freshwater resource exploitation throughout the period ~10,200–3700 cal BC, and presents the available evidence for the existence of dietary offsets in the 14C dates obtained. We have obtained human skeletal material from 54 Epipaleolithic to Mesolithic period individuals and 267 Neolithic to Eneolithic individuals, from 13 cemeteries, since our research in Ukraine began in 1992. Here, we present the initial results of stable isotope analysis of Eneolithic individuals from the Igren VIII cemetery alongside the Epipaleolithic to Eneolithic samples that have previously been analyzed. When contrasted against the evidence from the prehistoric fauna and fish remains studied, and modern fish species from the Dnieper region, we continue to see variability in diets at the population level, both internally and across cemeteries. We also observed temporal variability in human diets across these chronological periods. The fish samples (both archaeological and modern) show a wide range of isotope ratios for both δ13C and δ15N, which could prove significant when interpreting the dietary sources being exploited. This information directly informs the 14C dating program as an inherent degree of complexity is introduced into the dating of individuals whose diets combine freshwater and terrestrial sources in differing quantities and at differing temporal and/or spatial scales (e.g. Bronk Ramsey et al. 2014).
Introduction
Despite efficacious modern induction combination therapies a subset of myeloma patients have high-risk disease which manifests as either primary refractory disease or early relapse ...following initial response. The presence of known molecular high-risk lesions explain the majority of these cases but understanding the factors influencing the poor phenotypic outcome for the remainder will help us improve outcomes further. This exploratory analysis of the Myeloma XI+ trial aimed to understand the population of patients with phenotypic high-disease in the context of carfilzomib and lenalidomide induction therapy.
Methods
The UK NCRI Myeloma XI trial is a phase III randomised controlled trial that recruited 2568 newly diagnosed transplant eligible patients, of which 526 were randomised to receive the induction combination KRdc comprising carfilzomib (K, 36mg/m2 IV d1-2, 8-9,15-16 (20mg/m2 #1d1-2)), lenalidomide (R, 25mg PO d1-21), dexamethasone (d, 40mg PO d1-4,8-9,15-16) and cyclophosphamide (c, 500mg PO d1,8) as part of an adaptive trial design. Induction therapy was planned for a minimum of 4 cycles or to maximum response prior to autologous stem cell transplant (ASCT). There was a subsequent randomisation to lenalidomide maintenance or observation at 3 months post ASCT.
Primary refractory disease was defined as not achieving at least a minimal response (MR) at maximum response after at least 4 cycles of induction therapy or progression at any time during induction regardless of initial response. Early relapse (ER) after ASCT was defined as progression within 12 months of ASCT. Molecular risk was defined as the presence of one (high risk) or more than one (ultra-high risk) of the following lesions: del(17p), gain(1q), t(4,14), t(14;16) or t(14;20).
Results
The incidence of primary refractory disease with the KRdc combination was very low. Only 8/526 (1.5%) patients were primary refractory, all having progression during induction therapy with a median progression free survival of only 126 days. The number of patients is too small to draw any firm conclusions regarding the characteristics associated with primary refractory disease.
401/526 (76%) of patients underwent high dose melphalan and ASCT on trial after KRdc induction. Those that did not proceed to ASCT on trial were either ineligible, mostly due to not completing the minimum required induction therapy, or were deemed not fit to undergo the procedure based on patient/clinician decision. Of those patients who underwent ASCT, 36/401 (9.0%) relapsed within 12 months (ER). These ER patients had both a shorter PFS2 and second PFS suggesting a continued association with adverse outcome beyond first line therapy.
Patients in the ER group were compared with those patients not relapsing until beyond 12 months after ASCT (nER). There was no difference in the sex, age or paraprotein or light chain sub-type of patients. There was evidence of a greater impact of bone marrow disease burden in the ER group with a lower haemoglobin (median 99 g/L vs 115, p = 0.0216), lymphocyte count (1.3 x10^9/L vs 1.8, p = 0.0012) and platelet count (187 x10^9/L vs 252, p = 0.0049) at baseline. Median bone marrow aspirate plasma cell infiltration was ER 33% vs nER 23%. There were no significant differences in ISS stage (ER ISS I 19%, II 50%, III 22%, nER ISS I 35%, II 36%, III 22%, p = 0.1434), lactate dehydrogenase, albumin or beta-2 microglobulin.
Patients in the ER group were less likely to have received lenalidomide maintenance (ER 12/36 33% vs nER 222/365 61%). For some (4/36) not receiving lenalidomide was due to relapse occurring prior to reaching the maintenance randomisation point (100 days post-ASCT). For those with available data 75% of patients in the ER group had molecular high (50%) or ultra-high (25%) risk disease, whilst 25% had standard risk using the trial definition. The individual lesions accounting for high-risk status were: gain(1q) in ER 42% vs nER 35%; t(4;14) ER 50% vs nER 10%; del(17p) ER 8% vs nER 7%.
Discussion
The combination of a second-generation immunomodulatory agent and proteasome inhibitor in the KRdc induction regimen is associated with deep responses and only a very small proportion of patients have primary refractory disease. Early relapse after KRdc and ASCT occurred in 9% of patients and was associated with high bone marrow disease burden and molecular high-risk features.
Pawlyn: Amgen: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Davies: Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Menzies: Celgene / BMS: Research Funding; Amgen: Research Funding; Merck Sharpe and Dohme: Research Funding. Henderson: BMS / Celgene: Research Funding; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Cook: Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Jenner: BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy. Jones: Janssen: Honoraria; BMS/Celgene: Other: Conference fees. Kaiser: AbbVie: Consultancy; Takeda: Consultancy, Other: Educational support; Seattle Genetics: Consultancy; Amgen: Honoraria; Pfizer: Consultancy; Karyopharm: Consultancy, Research Funding; GSK: Consultancy; Janssen: Consultancy, Other: Educational support, Research Funding; BMS/Celgene: Consultancy, Other: Travel support, Research Funding. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Cairns: Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Jackson: celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; J and J: Consultancy, Honoraria, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau.
The KRdc combination is off label
The hillforts of the Oxfordshire Ridgeway in south-central England have been interpreted as central places in the Early/Middle Iron Age, ca. 600–100 BCE, serving, among other functions, to integrate ...the management of animals, particularly sheep, between the upland Chalk downs and the adjacent low-lying Vale of the White Horse. Since these landforms differ geologically and pedologically, they lead to distinct isotopic ratios in the biosphere and so present the potential to investigate animal management practices in some detail. Here, we report the results of a multi-isotope study on domestic fauna (cattle, sheep and pig) within a very constrained study area, with the aim of testing the hypothesis that the Ridgeway's hillforts were placed to control and coordinate the movement of sheep between the Chalk and the Vale. However, the results suggest a different scenario. Bone collagen δ15N results indicate that cattle and sheep were both kept locally. Strontium isotopes, conversely, indicate that, while sheep and pigs were raised locally, cattle appear to have been mainly kept in the Vale during at least the first year of their lives. The apparent discrepancy between the two isotopes can be reconciled by the different periods of life represented by enamel and bone collagen measurements, with the movement of cattle onto the Ridgeway in their second or third year of life. Sequential measurements of δ13C and δ15N in dentine, and of δ13Cc and δ18Oc in enamel, provide further detail on the management of cattle, and offer some support for the above scenario. Early/Middle Iron Age stock-keeping in south-central England was complex, being integrated in some respects but distinct in others. The study demonstrates the level of detail it is possible to achieve with a multi-isotope approach to animal management practices in prehistory. The focus on a micro-region contrasts with, or rather complements, studies addressing larger-scale movement of animals in the past.
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•Multi-isotope study of British Iron Age fauna gives insights into animal management.•Isotopic discrepancies reconciled by the different ages represented by teeth and bone.•Sheep and pigs were mainly raised locally, while cattle had more complex life-histories.•Cattle management was integrated over a very small spatial scale.
Background
Although the median age of patients with newly diagnosed multiple myeloma (MM) is 70-74 years, recruitment of frail older patients to clinical trials is poor. The International Myeloma ...Working Group (IMWG) frailty score predicts survival, adverse events and treatment tolerability using age, the Katz Activity of Daily Living, the Lawton Instrumental Activity of Daily Living, and the Charlson Comorbidity Index, rather than age alone. Despite IMWG score prognostic biomarker capability, to date no evidence exists of its predictive biomarker potential. The UK-MRA Myeloma Risk Profile (MRP) has also been shown in both clinical trial and real-world populations to be a prognostic biomarker in transplant ineligible patients but prospective comparisons of the two scores have not been previously conducted.
Study Design/Methods
The FiTNEss trial (Myeloma XIV, NCT03720041, Figure 1A) is a UK-MRA phase III, multi-centre, randomised controlled trial for newly diagnosed MM patients not suitable for stem cell transplant. The primary objectives are
1) to compare early treatment cessation (<60 days from randomisation) between patients randomised to standard (reactive) and frailty-adjusted (adaptive, based on IMWG score) induction therapy delivery with the triplet ixazomib, lenalidomide and dexamethasone (IRd)
2) to compare progression free survival for maintenance lenalidomide plus placebo (R) and lenalidomide plus ixazomib (IR).
The FiTNEss trial is designed as an all-comers study with few exclusion criteria other than necessary for safety including some haematological and biochemical parameters, but there is no exclusion based on renal function. Patients with grade 2 or greater baseline peripheral neuropathy, current systemic infection or recent surgery or other cancer are excluded. Here we report the demographics for the first patients recruited, including IMWG frailty assessments and MRP to demonstrate the feasibility of recruiting frail patients to randomised phase III clinical trials.
Results
The FiTNEss trial opened on 04/08/2020 during the second wave of the COVID-19 pandemic in the UK. At the time of data cut off (14/07/2021) recruitment is active at 84 sites, with 180 patients randomised.
Baseline characteristics for the randomised patients are shown in Figure 1B. The median age of patients is 77 years (range 64, 93) with 36.1% aged 76-80 and 26.1% over 80. In keeping with the older patient population 26.6% have an ECOG performance status of 2 or 3 and 31.7% ISS stage III. The IMWG frailty classification at baseline is FIT 43/180 (23.9%), UNFIT 53/180 (29.4%) and FRAIL 84/180 (46.7%).
The effect of using age groups on the definition of patient frailty was explored. The IMWG frailty score defines all patients over 80 as FRAIL whilst an age of 76-80 contributes one point to the score. An analysis of patients' frailty was repeated with the contribution of age removed. For those aged over 80 years (n=47, 100% FRAIL) we found that 20 (42.6%) would have been re-classified as FIT and 18 (38.3%) as UNFIT, with only 9 (19.2%) retaining the FRAIL category. For those aged 76-80 (n=65, 53.8% UNFIT, 46.2% FRAIL) all 35 patients previously classified as UNFIT became FIT (53.8%) whilst 19 (29.2%) classed as FRAIL became UNFIT with 11 (16.9%) remaining FRAIL.
The MRP classification, using age as a continuous variable, was Low-risk 45/180 (25.0%), Medium-risk 46/180 (25.6%), High-risk 75/180 (41.7%) and not available for 14/180 (7.8%) patients. Concordance between the IMWG frailty score and the MRP occurred in 48.9% of patients (88/180). 37.2% of FIT patients were classified as MRP Low-risk, 32.1% of UNFIT patients as MRP Medium-risk and 65.5% of FRAIL patients as MRP High-risk.
Discussion
The FiTNEss trial demonstrates the feasibility of recruiting older, less fit patients to clinical trials. Recruitment of patients classified as FRAIL was very high despite the COVID pandemic, likely due to the all-oral nature of the regimen under investigation enabling patients to avoid attendance at hospital day units for treatment and associated exposure risk. In the population recruited to date we found age to be a key contributor to the FRAIL category of the IMWG frailty score. Concordance between IMWG frailty score and MRP was highest in FRAIL/High-risk patients. The first interim analysis of the primary objectives is planned when 50% of required participants for R1 have reached 60 days post R1, which is anticipated in Q2 of 2022.
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Cook: Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Pawlyn: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. Royle: BMS: Research Funding; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Coulson: BMS / Celgene: Honoraria; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Jenner: BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy. Kishore: Sanofi: Other: Attending fees; Celgene: Other: Attending fees; Takeda: Other: Attending fees; Jannsen: Other: Attending fees. Rabin: BMS / Celgene: Consultancy, Honoraria, Other: Travel support for meetings; Takeda: Consultancy, Honoraria, Other: Travel support for meetings; Janssen: Consultancy, Honoraria, Other: Travel support for meetings. Best: BMS/Celgene: Research Funding; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Gillson: BMS / Celgene: Research Funding; Meck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Henderson: Takeda: Research Funding; Amgen: Research Funding; Merck Sharpe and Dohme: Research Funding; BMS / Celgene: Research Funding. Olivier: Merck Sharpe and Dohme: Research Funding; Takeda: Research Funding; Amgen: Research Funding; Celgene / BMS: Research Funding. Kaiser: AbbVie: Consultancy; GSK: Consultancy; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy; Takeda: Consultancy, Other: Educational support; Janssen: Consultancy, Other: Educational support, Research Funding; BMS/Celgene: Consultancy, Other: Travel support, Research Funding. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jones: Janssen: Honoraria; BMS/Celgene: Other: Conference fees. Cairns: Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Jackson: celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; J and J: Consultancy, Honoraria, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau.
Frailty-score adapted dosing strategies
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