DYED-IN-THE-WOOL: THE IMPACT OF OCCUPATIONAL BEHAVIOUR AND THE ENVIRONMENT ON SMALL URBAN AND RURAL COMMUNITIES IN FLANDERS, C. 1200-1860 AD

This thesis presents a bioarchaeological study of six cemetery populations from Flanders (Belgium), dating from the medieval to early modern periods. The six sites represent populations from different regions/contexts (coastal, inland, small-urban and one high-status group), and through a multi-faceted study incorporating historical, archaeological and osteological evidence, provides the opportunity to explore the impact of socioeconomic and environmental conditions on the health status of individuals working within rural and small urban habitats between the late 12th and 19th centuries. In order to interpret inter- and intra-population variability, patterns of mortality, stature, diseases and activity markers (entheseal changes or EC) were assessed to investigate the consequences of a physically active lifestyle in an economically important and dynamic period. Historical socioeconomic research detailed the significance of Flanders in the production and trade of wool, linen, cloth, and specified the labour-intensive cultivation of flax and other crops that instigated a major impact on the working lives of both citizens and peasants. The analysis of EC supports the regional and gender labour differentiation between coastal and inland Flanders, whilst the palaeopathological investigation further indicates the consequences of the environment on health, especially upon those residing in a riverine, coastal or polder area. This research demonstrates the complementary and interdisciplinary nature of integrating a bioarchaeological study within a historical socio-economic framework, and elucidates, not only the impact of an arduous lifestyle on working individuals, but also the vulnerability of the people across status groups to the environment

Effect of the UK government's 2-week target on waiting times in women with breast cancer in southeast England

A government target of a maximum 2-week wait for women referred urgently with suspected breast cancer was introduced in April 1999. We have assessed changes in the distributions of waiting times and the proportions of cases meeting proposed targets before and after this date, using clinical audit data on 5750 women attending 19 hospitals in southeast England during the period July 1997-December 2000, who were subsequently found to have breast cancer. The proportion of cases being seen within 2 weeks of referral rose from 66.0 to 75.2%, and the median wait to first appointment fell from 13.6 to 12.3 days, following the introduction of the government target. The proportion of cases waiting 5 weeks or less between first hospital appointment and treatment fell from 83.8 to 80.3%, and median waits for treatment increased from 21.4 to 24.1 days. We also examined the effects on waiting times of various sociodemographic and care related factors. A total of 85.7% of screening cases vs 67.9% of symptomatic cases were seen within 2 weeks, and 95.0% of cases treated with tamoxifen received treatment within 5 weeks, as opposed to 77.6% of cases treated with surgery, 81.2% of chemotherapy cases and 52.8% of radiotherapy cases. While waiting times from GP referral to first hospital appointment have improved since the introduction of the government target, times from first appointment to treatment have increased, and consequently total waiting times have changed little

Proposed therapeutic range of treosulfan in reduced toxicity pediatric allogeneic hematopoietic stem cell transplant conditioning: results from a prospective trial

Treosulfan is given off‐label in pediatric allogeneic hematopoietic stem cell transplant. This study investigated treosulfan's pharmacokinetics (PKs), efficacy, and safety in a prospective trial. Pediatric patients (n = 87) receiving treosulfan‐fludarabine conditioning were followed for at least 1 year posttransplant. PKs were described with a two‐compartment model. During follow‐up, 11 of 87 patients died and 12 of 87 patients had low engraftment (≤ 20% myeloid chimerism). For each increase in treosulfan area under the curve from zero to infinity (AUC(0‐∞)) of 1,000 mg hour/L the hazard ratio (95% confidence interval) for mortality increase was 1.46 (1.23–1.74), and the hazard ratio for low engraftment was 0.61 (0.36–1.04). A cumulative AUC(0‐∞) of 4,800 mg hour/L maximized the probability of success (> 20% engraftment and no mortality) at 82%. Probability of success with AUC(0‐∞) between 80% and 125% of this target were 78% and 79%. Measuring PK at the first dose and individualizing the third dose may be required in nonmalignant disease

Allogeneic hematopoietic stem cell transplantation for severe, refractory juvenile idiopathic arthritis.

Patients with juvenile idiopathic arthritis (JIA) can experience a severe disease course, with progressive destructive polyarthritis refractory to conventional therapy with disease-modifying antirheumatic drugs including biologics, as well as life-threatening complications including macrophage activation syndrome (MAS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative immunomodulatory strategy for patients with such refractory disease. We treated 16 patients in 5 transplant centers between 2007 and 2016: 11 children with systemic JIA and 5 with rheumatoid factor-negative polyarticular JIA; all were either refractory to standard therapy, had developed secondary hemophagocytic lymphohistiocytosis/MAS poorly responsive to treatment, or had failed autologous HSCT. All children received reduced toxicity fludarabine-based conditioning regimens and serotherapy with alemtuzumab. Fourteen of 16 patients are alive with a median follow-up of 29 months (range, 2.8-96 months). All patients had hematological recovery. Three patients had grade II-IV acute graft-versus-host disease. The incidence of viral infections after HSCT was high, likely due to the use of alemtuzumab in already heavily immunosuppressed patients. All patients had significant improvement of arthritis, resolution of MAS, and improved quality of life early following allo-HSCT; most importantly, 11 children achieved complete drug-free remission at the last follow-up. Allo-HSCT using alemtuzumab and reduced toxicity conditioning is a promising therapeutic option for patients with JIA refractory to conventional therapy and/or complicated by MAS. Long-term follow-up is required to ascertain whether disease control following HSCT continues indefinitely

The use of contextualised standardised client simulation to develop clinical reasoning in final year veterinary students

Clinical reasoning is an important skill for veterinary students to develop before graduation. Simulation has been studied in medical education as a method for developing clinical reasoning in students, but evidence supporting it is limited. This study involved the creation of a contextualized, standardized client simulation session that aimed to improve the clinical reasoning ability and confidence of final-year veterinary students. Sixty-eight participants completed three simulated primary-care consultations, with the client played by an actor and the pet by a healthy animal. Survey data showed that all participants felt that the session improved their clinical decision-making ability. Quantitative clinical reasoning self-assessment, performed using a validated rubric, triangulated this finding, showing an improvement in students’ perception of several components of their clinical reasoning skill level from before the simulation to after it. Blinded researcher analysis of the consultation video recordings found that students showed a significant increase in ability on the history-taking and making-sense-of-data (including formation of a differential diagnosis) components of the assessment rubric. Thirty students took part in focus groups investigating their experience with the simulation. Two themes arose from thematic analysis of these data: variety of reasoning methods and “It’s a different way of thinking.” The latter highlights differences between the decision making students practice during their time in education and the decision making they will use once they are in practice. Our findings suggest that simulation can be used to develop clinical reasoning in veterinary students, and they demonstrate the need for further research in this area

Bilateral Dorsal Cochlear Nucleus Lesions Prevent Acoustic-Trauma Induced Tinnitus in an Animal Model

Animal experiments suggest that chronic tinnitus (“ringing in the ears”) may result from processes that overcompensate for lost afferent input. Abnormally elevated spontaneous neural activity has been found in the dorsal cochlear nucleus (DCN) of animals with psychophysical evidence of tinnitus. However, it has also been reported that DCN ablation fails to reduce established tinnitus. Since other auditory areas have been implicated in tinnitus, the role of the DCN is unresolved. The apparently conflicting electrophysiological and lesion data can be reconciled if the DCN serves as a necessary trigger zone rather than a chronic generator of tinnitus. The present experiment used lesion procedures identical to those that failed to decrease pre-existing tinnitus. The exception was that lesions were done prior to tinnitus induction. Young adult rats were trained and tested using a psychophysical procedure shown to detect tinnitus. Tinnitus was induced by a single unilateral high-level noise exposure. Consistent with the trigger hypothesis, bilateral dorsal DCN lesions made before high-level noise exposure prevented the development of tinnitus. A protective effect stemming from disruption of the afferent pathway could not explain the outcome because unilateral lesions ipsilateral to the noise exposure did not prevent tinnitus and unilateral lesions contralateral to the noise exposure actually exacerbated the tinnitus. The DCN trigger mechanism may involve plastic circuits that, through loss of inhibition, or upregulation of excitation, increase spontaneous neural output to rostral areas such as the inferior colliculus. The increased drive could produce persistent pathological changes in the rostral areas, such as high-frequency bursting and decreased interspike variance, that comprise the chronic tinnitus signal

Metacarpal trabecular bone varies with distinct hand-positions used in hominid locomotion

Trabecular bone remodels during life in response to loading and thus should, at least in part, reflect potential variation in the magnitude, frequency and direction of joint loading across different hominid species. Here we analyse the trabecular structure across all non-pollical metacarpal distal heads (Mc2-5) in extant great apes, expanding on previous volume of interest and whole-epiphysis analyses that have largely focussed on only the first or third metacarpal. Specifically, we employ both a univariate statistical mapping and a multivariate approach to test for both inter-ray and interspecific differences in relative trabecular bone volume fraction (RBV/TV) and degree of anisotropy (DA) in Mc2-5 subchondral trabecular bone. Results demonstrate that while DA values only separate Pongo from African apes (Pan troglodytes, Pan paniscus, Gorilla gorilla), RBV/TV distribution varies with the predicted loading of the metacarpophalangeal (McP) joints during locomotor behaviours in each species. Gorilla exhibits a relatively dorsal distribution of RBV/TV consistent with habitual hyper-extension of the McP joints during knuckle-walking, whereas Pongo has a palmar distribution consistent with flexed McP joints used to grasp arboreal substrates. Both Pan species possess a disto-dorsal distribution of RBV/TV, compatible with multiple hand postures associated with a more varied locomotor regime. Further inter-ray comparisons reveal RBV/TV patterns consistent with varied knuckle-walking postures in Pan species in contrast to higher RBV/TV values toward the midline of the hand in Mc2 and Mc5 of Gorilla, consistent with habitual palm-back knuckle-walking. These patterns of trabecular bone distribution and structure reflect different behavioural signals that could be useful for determining the behaviours of fossil hominins

On the Functional Significance of the P1 and N1 Effects to Illusory Figures in the Notch Mode of Presentation

The processing of Kanizsa figures have classically been studied by flashing the full “pacmen” inducers at stimulus onset. A recent study, however, has shown that it is advantageous to present illusory figures in the “notch” mode of presentation, that is by leaving the round inducers on screen at all times and by removing the inward-oriented notches delineating the illusory figure at stimulus onset. Indeed, using the notch mode of presentation, novel P1and N1 effects have been found when comparing visual potentials (VEPs) evoked by an illusory figure and the VEPs to a control figure whose onset corresponds to the removal of outward-oriented notches, which prevents their integration into one delineated form. In Experiment 1, we replicated these findings, the illusory figure was found to evoke a larger P1 and a smaller N1 than its control. In Experiment 2, real grey squares were placed over the notches so that one condition, that with inward-oriented notches, shows a large central grey square and the other condition, that with outward-oriented notches, shows four unconnected smaller grey squares. In response to these “real” figures, no P1 effect was found but a N1 effect comparable to the one obtained with illusory figures was observed. Taken together, these results suggest that the P1 effect observed with illusory figures is likely specific to the processing of the illusory features of the figures. Conversely, the fact that the N1 effect was also obtained with real figures indicates that this effect may be due to more global processes related to depth segmentation or surface/object perception