Factors influencing the radiocarbon dating of human skeletal remains from the Dnieper River system: Archaeological and stable isotope evidence of diet from the Epipaleolithic to Eneolithic periods

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

Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma (FiTNEss (UK-MRA Myeloma XIV Trial)): a study protocol for a randomised phase III trial

INTRODUCTION: Multiple 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 ANALYSIS: Frailty-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 DISSEMINATION: Ethical 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

COVID-19 trajectories among 57 million adults in England: a cohort study using electronic health records

BACKGROUND: Updatable estimates of COVID-19 onset, progression, and trajectories underpin pandemic mitigation efforts. To identify and characterise disease trajectories, we aimed to define and validate ten COVID-19 phenotypes from nationwide linked electronic health records (EHR) using an extensible framework. METHODS: In this cohort study, we used eight linked National Health Service (NHS) datasets for people in England alive on Jan 23, 2020. Data on COVID-19 testing, vaccination, primary and secondary care records, and death registrations were collected until Nov 30, 2021. We defined ten COVID-19 phenotypes reflecting clinically relevant stages of disease severity and encompassing five categories: positive SARS-CoV-2 test, primary care diagnosis, hospital admission, ventilation modality (four phenotypes), and death (three phenotypes). We constructed patient trajectories illustrating transition frequency and duration between phenotypes. Analyses were stratified by pandemic waves and vaccination status. FINDINGS: Among 57 032 174 individuals included in the cohort, 13 990 423 COVID-19 events were identified in 7 244 925 individuals, equating to an infection rate of 12·7% during the study period. Of 7 244 925 individuals, 460 737 (6·4%) were admitted to hospital and 158 020 (2·2%) died. Of 460 737 individuals who were admitted to hospital, 48 847 (10·6%) were admitted to the intensive care unit (ICU), 69 090 (15·0%) received non-invasive ventilation, and 25 928 (5·6%) received invasive ventilation. Among 384 135 patients who were admitted to hospital but did not require ventilation, mortality was higher in wave 1 (23 485 [30·4%] of 77 202 patients) than wave 2 (44 220 [23·1%] of 191 528 patients), but remained unchanged for patients admitted to the ICU. Mortality was highest among patients who received ventilatory support outside of the ICU in wave 1 (2569 [50·7%] of 5063 patients). 15 486 (9·8%) of 158 020 COVID-19-related deaths occurred within 28 days of the first COVID-19 event without a COVID-19 diagnoses on the death certificate. 10 884 (6·9%) of 158 020 deaths were identified exclusively from mortality data with no previous COVID-19 phenotype recorded. We observed longer patient trajectories in wave 2 than wave 1. INTERPRETATION: Our analyses illustrate the wide spectrum of disease trajectories as shown by differences in incidence, survival, and clinical pathways. We have provided a modular analytical framework that can be used to monitor the impact of the pandemic and generate evidence of clinical and policy relevance using multiple EHR sources. FUNDING: British Heart Foundation Data Science Centre, led by Health Data Research UK

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

Background: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. Methods: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. Findings: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96–1·28). Interpretation: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. Funding: National Institute for Health Research Health Services and Delivery Research Programme

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

BACKGROUND: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. METHODS: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. FINDINGS: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96-1·28). INTERPRETATION: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. FUNDING: National Institute for Health Research Health Services and Delivery Research Programme

Early life histories: a study of past childhood diet and health using stable isotopes and enamel hypoplasia

The δδ13C and δ15N composition of incremental segments of tooth dentine was used to infer infant and childhood diet in a post-medieval London population, and a hunting and gathering Mesolithic/Neolithic group from Latvia. Health was analysed using defects on the tooth enamel caused by stress, termed enamel hypoplasia. The populations, which differ markedly in their economy, diet and health, were selected because of the difference in childhood experiences between the two groups. The results were used to consider questions about childhood, including how early diet may have been influenced by social factors such as class or status, the effect this could have on population dynamics and how childhood diet and health are related. The results show that the London individuals were rarely breastfed beyond 6 months and in some instances not at all. A small isotopic difference between males and females was observed which could be caused by dietary or physiological differences. The peak incidence of hypoplasia may be related to developmental patterns, rather than stress caused by weaning. The Zvejnieki individuals had a slightly longer breastfeeding duration. Those buried with pendants consumed a different diet in childhood to those without pendants, suggesting a complex social system, possibly indicating that diet was related to the role a person had within the community. There is a suggestion diet may have shifted between the Middle Mesolithic and Late Neolithic, although not dramatically. Neither population have elevated δ13C often associated with breastfeeding. The early life histories of the groups are not compared directly, but general observations concerning the children’s lives are considered. It is concluded that economy is not a reliable predictor of infant feeding strategies, as hunter-gatherers provide children with solid foods at a similar time to industrial groups. Intra-population variability was found to be a feature of all socio-economic groups.</p

Mirror-writing in children and the right-writing rule: critically testing the implicit writing rule using novel stimuli.

Mirror-writing is the phenomenon in which letters, words or digits are written in reverse direction and can be read normally when held to a mirror. Unintentional mirror-writing is frequently observed in young children learning to write but typically disappears by the age of 8. The majority of rightward scripts, such as the English alphabet, contain characters that are predominantly right-facing (e.g. c) or have a vertical line to the left of a distinctive feature (e.g. b). Fischer (2011) proposed an implicit writing rule after observing that left-facing characters (LFCs) are more frequently mirror-written than right-facing characters (RFCs), theorising that children acquire a right-writing rule during literacy development. Moving beyond the results found by Fischer (2011) the present study taught children a set of novel stimuli, rather than using naturally occurring and thus uncontrollable characters, to test whether LFCs really are more frequently mirror-written than RFCs. To explore these results further it was also hypothesised that children with greater language experience, who have therefore acquired an implicit writing rule, will be more likely to mirror-write LFCs. On the other hand, children with less experience with language will not have acquired this implicit writing rule so will not show this pattern of mirror-writing, but in general will mirror-write more frequently. The findings obtained in this study did provide support for Fischer’s (2011) implicit writing rule and children are statistically more likely to mirror-write LFCs than RFCs. There are also significant findings to suggest that children with a greater experience with language mirror-write less overall. However, mixed findings when looking at the patterns of mirror-writing across the experience with language groups has led this study to suggest that there may be factors other than acquiring a right-writing rule during literacy development, for instance motor tendencies, which causes this bias in mirror-writing

Early life histories: a study of past childhood diet and health using stable isotopes and enamel hypoplasia

The &delta;&delta;13C and &delta;15N composition of incremental segments of tooth dentine was used to infer infant and childhood diet in a post-medieval London population, and a hunting and gathering Mesolithic/Neolithic group from Latvia. Health was analysed using defects on the tooth enamel caused by stress, termed enamel hypoplasia. The populations, which differ markedly in their economy, diet and health, were selected because of the difference in childhood experiences between the two groups. The results were used to consider questions about childhood, including how early diet may have been influenced by social factors such as class or status, the effect this could have on population dynamics and how childhood diet and health are related. The results show that the London individuals were rarely breastfed beyond 6 months and in some instances not at all. A small isotopic difference between males and females was observed which could be caused by dietary or physiological differences. The peak incidence of hypoplasia may be related to developmental patterns, rather than stress caused by weaning. The Zvejnieki individuals had a slightly longer breastfeeding duration. Those buried with pendants consumed a different diet in childhood to those without pendants, suggesting a complex social system, possibly indicating that diet was related to the role a person had within the community. There is a suggestion diet may have shifted between the Middle Mesolithic and Late Neolithic, although not dramatically. Neither population have elevated &delta;13C often associated with breastfeeding. The early life histories of the groups are not compared directly, but general observations concerning the children’s lives are considered. It is concluded that economy is not a reliable predictor of infant feeding strategies, as hunter-gatherers provide children with solid foods at a similar time to industrial groups. Intra-population variability was found to be a feature of all socio-economic groups.This thesis is not currently available in ORA