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James Walker, John Lee and Stephen Broadberry synthesise and analyse ancient sources to address three fascinating questions: What can Domesday Book tell us about medieval England and Wales? How can we estimate medieval populations? What was the size of the medieval economy?

SARS-CoV-2 antibody levels associated with reduced hospitalization risk remain undefined. Our outpatient COVID-19 convalescent plasma (CCP), placebo-controlled trial observed SARS-CoV-2 antibody levels decreasing 22-fold from matched donor units into post-transfusion seronegative recipients. Unvaccinated recipients were jointly stratified by a) early or late transfusion (≤ 5 or >5 days from symptom onset) and b) high or low post-transfusion SARS-CoV-2 antibody levels (< or ≥ geometric mean). Early treatment with high post-transfusion antibody levels reduced hospitalization risk-0/102 (0%) compared to all other CCP recipients-17/370 (4.6%; Fisher exact p=0.03) and to all control plasma recipients-35/461 (7.6%; Fisher exact p=0.001). A similar donor upper/lower antibody level and early late transfusion stratified analyses indicated significant hospital risk reduction. Pre-transfusion nasal viral loads were similar in CCP and control recipients regardless of hospitalization outcome. Therapeutic CCP should comprise the upper 30% of donor antibody levels to provide effective outpatient use for immunocompromised and immunocompetent outpatients.

Inhalation anthrax has three clinical stages: early-prodromal, intermediate-progressive, and late-fulminant. We report the comprehensive characterization of anthrax toxins, including total protective antigen (PA), total lethal factor (LF), total edema factor (EF), and their toxin complexes, lethal toxin and edema toxin in plasma, during the course of inhalation anthrax in 23 cynomolgus macaques. The toxin kinetics were predominantly triphasic with an early rise (phase-1), a plateau/decline (phase-2), and a final rapid rise (phase-3). Eleven animals had shorter survival times, mean±standard deviation of 58.7±7.6 hours (fast progression), 11 animals had longer survival times, 113±34.4 hours (slow progression), and one animal survived. Median (lower–upper quartile) LF levels at the end-of-phase-1 were significantly higher in animals with fast progression [138 (54.9–326) ng/mL], than in those with slow progression [23.8 (15.6–26.3) ng/mL] (p = 0.0002), and the survivor (11.1 ng/mL). The differences were also observed for other toxins and bacteremia. Animals with slow progression had an extended phase-2 plateau, with low variability of LF levels across all time points and animals. Characterization of phase-2 toxin levels defined upper thresholds; critical levels for exiting phase-2 and entering the critical phase-3, 342 ng/mL (PA), 35.8 ng/mL (LF), and 1.10 ng/mL (EF). The thresholds were exceeded earlier in animals with fast progression (38.5±7.4 hours) and later in animals with slow progression (78.7±15.2 hours). Once the threshold was passed, toxin levels rose rapidly in both groups to the terminal stage. The time from threshold to terminal was rapid and similar; 20.8±7.4 hours for fast and 19.9±7.5 hours for slow progression. The three toxemic phases were aligned with the three clinical stages of anthrax for fast and slow progression which showed that anthrax progression is toxin- rather than time-dependent. This first comprehensive evaluation of anthrax toxins provides new insights into disease progression.

Ticagrelor is an oral P2YIn this randomized, double-blind, placebo-controlled, phase 1 trial, we evaluated intravenous PB2452, a monoclonal antibody fragment that binds ticagrelor with high affinity, as a ticagrelor reversal agent. We assessed platelet function in healthy volunteers before and after 48 hours of ticagrelor pretreatment and again after the administration of PB2452 or placebo. Platelet function was assessed with the use of light transmission aggregometry, a point-of-care P2YOf the 64 volunteers who underwent randomization, 48 were assigned to receive PB2452 and 16 to receive placebo. After 48 hours of ticagrelor pretreatment, platelet aggregation was suppressed by approximately 80%. PB2452 administered as an initial intravenous bolus followed by a prolonged infusion (8, 12, or 16 hours) was associated with a significantly greater increase in platelet function than placebo, as measured by multiple assays. Ticagrelor reversal occurred within 5 minutes after the initiation of PB2452 and was sustained for more than 20 hours (P0.001 after Bonferroni adjustment across all time points for all assays). There was no evidence of a rebound in platelet activity after drug cessation. Adverse events related to the trial drug were limited mainly to issues involving the infusion site.In healthy volunteers, the administration of PB2452, a specific reversal agent for ticagrelor, provided immediate and sustained reversal of the antiplatelet effects of ticagrelor, as measured by multiple assays. (Funded by PhaseBio Pharmaceuticals; ClinicalTrials.gov number, NCT03492385.).

Aldosterone is an important mineralocorticoid responsible for fluid and electrolyte homeostasis produced by aldosterone synthase (CYP11B2). An aldosterone synthase inhibitor (ASI) may be a therapeutic option for primary aldosteronism-related conditions such as resistant hypertension. An ASI with sufficient selectivity for CYP11B2 versus the similar cortisol-producing enzyme CYP11B1 has remained elusive. PB6440 is a novel ASI that is potent and highly selective for CYP11B2. In vitro studies demonstrated 200-300-fold selectivity of PB6440 for human CYP11B2 compared to human CYP11B1. In single and multiple dose cynomolgus monkey studies of orally administered PB6440, dose-and concentration-dependent reduction of plasma aldosterone after ACTH challenge was observed with >90% reduction at higher doses. Consistent with its high selectivity, PB6440 had little effect on the CYP11B1 cortisol pathway. Plasma levels of cortisol, 11-deoxycortisol, and deoxycorticosterone, remained unchanged even at high doses of PB6440. Systolic and diastolic blood pressure was reduced in a dose-dependent manner. Circulating half-life of PB6440 was approximately 17 hours with high oral bioavailability. In summary, PB6440 is a highly selective ASI that demonstrated sustained aldosterone suppression for 14 days with no effect on the CYP11B1 pathway in non-human primates. In single and multiple dose studies, PB6440 appeared well tolerated, demonstrating good oral bioavailability, and a PK profile supportive of once daily dosing. These results suggest that PB6440 may be useful in humans as a novel therapeutic for treating hypertension or other conditions caused by excess aldosterone.

In 2017, 43.9% of US physicians reported symptoms of burnout. Poor electronic health record (EHR) usability and time-consuming data entry contribute to burnout. However, less is known about how modifiable dimensions of EHR use relate to burnout and how these associations vary by medical specialty. Using the KLAS Arch Collaborative’s large-scale nationwide physician (MD/DO) data, we used ordinal logistic regression to analyze associations between self-reported burnout and after-hours charting and organizational EHR support. We examined how these relationships differ by medical specialty, adjusting for confounders. Physicians reporting ≤ 5 hours weekly of after-hours charting were twice as likely to report lower burnout scores compared to those charting ≥6 hours (aOR: 2.43, 95% CI: 2.30, 2.57). Physicians who agree that their organization has done a great job with EHR implementation, training, and support (aOR: 2.14, 95% CI: 2.01, 2.28) were also twice as likely to report lower scores on the burnout survey question compared to those who disagree. Efforts to reduce after-hours charting and improve organizational EHR support could help address physician burnout.

Unimolecular decomposition pathways are challenging to address in transition-metal catalysis and have previously not been suppressed via incorporation into a solid support. Two robust metal-organic frameworks (IRMOF-10 and bio-MOF-100) are used for the architectural stabilization of a structurally well-defined gold(III) catalyst. The inherent rigidity of these materials is utilized to preclude a unimolecular decomposition pathway - reductive elimination. Through this architectural stabilization strategy, decomposition of the incorporated gold(III) catalyst in the metal-organic frameworks is not observed; in contrast, the homogeneous analogue is prone to decomposition in solution. Stabilization of the catalyst in these metal-organic frameworks precludes leaching and enables recyclability, which is crucial for productive heterogeneous catalysis.

One of the most important manuscripts surviving from thirteenth-century England, the corpus of documents known as the Hundred Rolls for Cambridge have been incomplete until the recent discovery of an additional roll. This invaluable volume replaces the previous inaccurate transcription by the record commission of 1818 and provides new translations and additional appendices. Shedding new light on important facets of business activity in thirteenth-century Cambridge, this volume makes a significant contribution to our knowledge of the early phases of capitalism. This unique text will be of interest to anyone working in the fields of economic and business history, entrepreneurship, philanthropy and medieval studies. A research monograph based on recently discovered historical documents, Compassionate Capitalism: Business and Community in Medieval England, by Casson et al, is also now available from Bristol University Press.

The chapter provides new translations of these previously unpublished documents.

Family dynasties were important players in the property market of medieval Cambridge, the Hundred Rolls reveal. Using a wide range of archival sources this chapter examines the inter family relationships and cross family connections of 23 families identified from the rolls, including the Bartons, Blancgernuns and Dunnings. Strategies by which families accumulated and extended their property portfolios are examined. Causes of family decline and family success are considered.

Chapter 3 analyses the economic topography of the town, building on the results presented in Chapter 2. It investigates how far occupations were specialised in different part of the town. It constructs profiles of all the Cambridge parishes, showing how many properties were located in each, how much rent those properties paid, to whom they paid it, who held the properties, and in some cases their occupation too. It is also possible to chart the spatial distribution of occupational names. Because of the missing roll, it is possible for the first time to provide a definitive account of all the parishes. This corrects a bias in previous topographical accounts, which have over-emphasised the north and west of the town at the expense of the south and east.

Haemaphysalis longicornis, the cattle tick or bush tick, has an extended distribution throughout Asia and the Pacific region, including China, Russia, the Republic of Korea (ROK), Japan, Australia, New Zealand, and the South Pacific islands. It is an obligate ectoparasite found commonly on medium to large sized wild and domestic animals, with humans as an accidental host. Haemaphysalis longicornis transmits a number of pathogens, including severe fever with thrombocytopenia syndrome and tick-borne encephalitis viruses, bacteria, helminths, and protozoans, that impact on veterinary (wild and domestic animals) and human health. Surveys of rickettsial pathogens associated with H. longicornis from China, the ROK, and Japan have resulted in the discovery of more than 35 incompletely characterized molecular isolates of Rickettsia. In response to the increased global threat of tick-borne rickettsial diseases, H. longicornis collected in the ROK and China were assessed in our laboratory and two additional Rickettsia spp. isolates (ROK-HL727 and XinXian HL9) were identified. These agents were fully characterized by multilocus sequence typing using partial gene fragment sequences of rrs, gltA, ompA, ompB, and sca4. Phylogenetic comparisons of these Rickettsia isolates with known Rickettsia species and other molecular isolates identified from H. longicornis were performed to better understand their interrelationships. Phylogenetic analysis of the sequences from these 5 gene fragments showed that ROK-HL727 was closely related to rickettsial isolates of H. longicornis previously reported from China, the ROK and Japan, but distinct from any currently recognized Rickettsia species. It therefore qualifies genetically as a new species, introduced herein as Candidatus Rickettsia longicornii. The XinXian-HL9 isolate detected from China was determined to be genetically similar to the human pathogen Rickettsia heilongjiangensis. People living and working in areas where H. longicornis is endemic should be aware of the potential for rickettsial diseases.

Aims The aims of the present study were to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-962212, a first-in-class factor XIa inhibitor, in Japanese and non-Japanese healthy subjects. Methods This was a randomized, placebo-controlled, double-blind, sequential, ascending-dose study of 2-h (part A) and 5-day (part B) intravenous (IV) infusions of BMS-962212. Part A used four doses (1.5, 4, 10 and 25 mg h-1 ) of BMS-962212 or placebo in a 6:2 ratio per dose. Part B used four doses (1, 3, 9 and 20 mg h-1 ) enrolling Japanese (n = 4 active, n = 1 placebo) and non-Japanese (n = 4 active, n = 1 placebo) subjects per dose. The PK, PD, safety and tolerability were assessed throughout the study. Results BMS-962212 was well tolerated; there were no signs of bleeding, and adverse events were mild. In parts A and B, BMS-962212 demonstrated dose proportionality. The mean half-life in parts A and B ranged from 2.04 to 4.94 h and 6.22 to 8.65 h, respectively. Exposure-dependent changes were observed in the PD parameters, activated partial thromboplastin time (aPTT) and factor XI clotting activity (FXI:C). The maximum mean aPTT and FXI:C change from baseline at 20 mg h-1 in part B was 92% and 90%, respectively. No difference was observed in weight-corrected steady-state concentrations, aPTT or FXI:C between Japanese and non-Japanese subjects (P > 0.05). Conclusion BMS-962212 has tolerability, PK and PD properties suitable for investigational use as an acute antithrombotic agent in Japanese or non-Japanese subjects.

Hypertension is associated with high morbidity and mortality. Blood pressure (BP) levels vary widely due to predictable biological rhythms and unpredictable environmental factors. Daily (circadian) rhythm characteristics are considered essential parameters for recognizing and treating increased risks in BP. Franz Halberg spent most of his academic career in cardiovascular research, focused on ambulatory monitoring and developing chronobiological methods for clinical application. To compare BP Variability (BPV), automatically monitored ambulatory BP around the clock at 30-60 min intervals in 20 human subjects was compared with telemetered circadian BP in rats after one-cell homozygous embryo-transfer into spontaneously hypertensive (SHR, pup:shr) or normotensive (WKY, pup:wky) rats' oviducts (embryos: s,w; oviduct-uterus: S,W) and cross-suckled at birth (nurses S,W). The circadian response peaked in the late afternoon hours in most human subjects and early morning hours in rats. Human circadian double amplitudes (2A) varied from 8 to 26 mm Hg with higher 2A in elder adults, and 3-8 mm Hg in rats with significantly higher fluctuations in SHR groups (7.5±0.7 for sSS, 8.3±0.6 for sSW vs. 4.7±0.3 mm Hg for wWW). The circaseptan 2A in the adolescents were 10±1 for SBP and 12±3 mm Hg for DBP, and sharp increased winter 2A (SBP 54; HR 48, both P

The development of LXR agonists for the treatment of coronary artery disease has been challenged by undesirable properties in animal models. Here we show the effects of an LXR agonist on lipid and lipoprotein metabolism and neutrophils in human subjects. BMS-852927, a novel LXRβ-selective compound, had favorable profiles in animal models with a wide therapeutic index in cynomolgus monkeys and mice. In healthy subjects and hypercholesterolemic patients, reverse cholesterol transport pathways were induced similarly to that in animal models. However, increased plasma and hepatic TG, plasma LDL-C, apoB, apoE, and CETP and decreased circulating neutrophils were also evident. Furthermore, similar increases in LDL-C were observed in normocholesterolemic subjects and statin-treated patients. The primate model markedly underestimated human lipogenic responses and did not predict human neutrophil effects. These studies demonstrate both beneficial and adverse LXR agonist clinical responses and emphasize the importance of further translational research in this area.

Commemoration can take the form of an action – a calling to remembrance, such as through prayer, or the form of an object – such as a memorial. Many studies of late medieval commemoration have tended to examine the latter, exploring particular monuments in particular contexts, mostly in churches and cathedrals, as well as considering different workshops, styles and patrons. They have focused on the product of commemoration. Most have taken a traditional approach to this subject, simply discussing the tomb, or the window, or the chantry without reflecting on the overall message. There were, however, a myriad of different commemorative enterprises available. The role of the monument in the context of remembrance, the benefactor, charity and prayer is here explored within the university town of Cambridge. Studies of towns, such as Bristol, are well known and in recent years there has been a revived interest in urban commemoration which has ‘opened up’ ideas on the bigger picture and how intercessory prayer dovetailed with investment in church building, most particularly the monument, to achieve salvation. New material on Boston, Coventry and York has revealed how urban elites and visitors sought appropriate commemorations for themselves and their families through a variety of differing and inter-connected strategies, while in London Christian Steer's study of St. James Garlickhithe has pieced together parts of the ‘commemoration jigsaw’ within this particular city parish, in which different forms of commemoration served the interests of the living and the dead. Individual monuments, too, are now receiving fresh interpretations. In medieval Cambridge, the range of religious institutions to which benefactors could make gifts and entrust their commemoration expanded significantly. A burgess living in the town shortly after 1200 could choose to make a benefaction to one of sixteen parish churches, to either religious house (or both), or to one of the two hospitals. By 1300, Cambridge residents could also select one (or more) of the six houses of mendicant friars, or another religious house or hospital, as possible recipients. By 1400, wealthy Cambridge citizens could also choose one of many guilds or several academic colleges to provide their intercessory services. Patterns of benefaction among medieval townspeople generally followed these trends, with new institutions commonly becoming the chief objects of attention. The town was distinctive in having the presence of an academic community which grew in size and wealth during the later Middle Ages.

Blood pressure (BP) fluctuates due to complex interactions between genetic factors and environmental stimulation. BP variability (BPV) is a physiological phenomenon, as a measure of hemodynamic conditions reflected in the autonomic nervous system. Daily (circadian) rhythms as biological time structures are considered essential parameters for recognizing and treating BP risk factors. Thus, ambulatory BP and heart rate (HR) were monitored (ABPM) in 11 normotensive (NT) in a free living, and 13 borderline hypertensive (BH) adults with Na and weight (WT, Kg) interventions in a freely moving lab environments, around the clock at 30-minute to hourly intervals. In the intervention study, circadian BP, HR, urinary aldosterone (Aldo, μg/h), creatinine (Cr), Na, K in mEq/h and Na/K ratio were compared. Data was analyzed by the linear least square rhythmometry method. All subjects showed significant circadian fluctuations in BP (mm Hg) and HR (beats/min). The circadian response peaked in the noon to late afternoon hours in the NT and in the reference stage of the intervention study. In NT, SBP: 111±2 with variability 14.6% and peak hr at 16:00; DBP: 74.0±1 with variability 16.0% and peak hr at 15:40; and HR: 64.3±2 with peak hr at 16:96 (-254°). In the intervention study with reference (I), Na restriction (II) and weight (WT) reduction (III) stages, SBP: 130±3.7; 130±1.7; 116±1.7 with variability (SBPV), 27.5, 31.4, and 25.4%; peak hrs at 16:26, 13:52; 12:24, respectively; DBP: 85±2.3; 83±2.2; 77±1.9 with variability (DBPV), 21.1, 26.4, 33.5%; peak hrs at 16:15, 18:29, 07:52, respectively; and HR: 64±2.1; 61±2.1; 66±2.3 with HRV, 30.2, 34.6, 28.3%; peak hrs at 15:07; 14:64, 14:55, respectively. Circadian UAldo: 0.63, 0.73, 0.58; UNa: 6.3, 2.9, 3.5; UK: 3.1, 3.1, 2.9; and WT: 89.9, 87.8, 83.2 in I, II, and III study stages, respectively. Thus, BP and HR, and their variabilities are the factors readjusted in the Na and WT reductions, and the peak shifted to earlier hours in the intervention. The variability, in the reference stage already higher than the NT levels, was not favorably changed with Na and WT interventions, although BP was normalized, especially following the WT reduction. Increased or shallow amplitudes may be predictive risk factors of vascular disease.

A clear and accessibly written guide to the medieval cloth-making trade in England.

It is widely believed that a preceptory (house and estate centre) of the Knights Templar was located in the township of Whitley, near Selby, only four miles from another preceptory at Temple Hirst. This article argues that documentary evidence, closely analysed, points to the site of the preceptory being 24 miles further east, at Weedley, near South Cave in the East Riding. The evidence includes references to lands at Wichele or Withele in the Templars’ inquest of 1185, and an inventory detailing possessions of the preceptory of Wythele in 1308. The location of the preceptory is examined alongside the changing organization of the Templars’ estates by the early-fourteenth century. Establishing the correct location of the preceptory is important in understanding more about the relationship between different Templar houses within the county, and highlights the potential for archaeological remains at the site of the preceptory.