An exciting hypothesis about the cerebellum is that its role is one of state estimation-a process that combines efferent copies of motor commands with afferent sensory signals to produce a representation of the current status of the peripheral motor system. Sensory inputs alone cannot provide a perfect state signal because of inevitable delays in their afferent pathways. We have recently reported the effects of transcranial magnetic stimulation (TMS) over the ipsilateral cerebellum as healthy subjects made rapid reaching movements towards visually defined targets (Miall et al. in PLoS Biology 5:2733-2744, 2007. Errors in the initial direction and in the final finger position of this reachto-target movement were consistent with the reaching movements being planned and initiated from an estimated hand position that was about 138 ms out of date. This interval is consistent with estimates of the delays in sensory motor pathways that would inform the central nervous system of the peripheral status. We now report new data using the same paradigm, testing the effects of varying the TMS stimulus train from one, two, or three pulses. We show that the errors in movement are relatively insensitive to the TMS pulse-train duration. The estimated time interval by which the hand position is mislocalized varied by only 12 ms as the TMS train duration increased by 100 ms. Thus, this interval is likely to reflect physiological processes within the cerebellum rather than the TMSstimulus duration. This new evidence supports our earlier claim that the cerebellum is responsible for predictively updating a central state estimate over an interval of about 120-140 ms. Dysfunction of the cerebellum, whether through disease or experimental procedures, leads to motor errors consistent with a loss of knowledge of the true state of the motor system.
Background: Data regarding incidence, prevalence and long-term outcomes of inflammatory bowel diseases in the UK are limited or outdated. Aims:To investigate incidence and prevalence of Crohn's disease and ulcerative colitis and risk of colorectal cancer and all-cause mortality in these diseases.Methods: Inflammatory bowel disease cases between 2000 and 2018 were identified from a national primary care database. Inflammatory bowel disease prevalence was forecast until 2025. The association between inflammatory bowel disease and colorectal cancer and all-cause mortality was investigated using age/sex-matched retrospective cohort studies. Hazard ratios were adjusted for age, sex, deprivation, comorbidity, smoking status and body mass index.Results: Ulcerative colitis prevalence increased from 390 to 570 per 100 000 population from 2000 to 2017. Prevalence of Crohn's disease increased from 220 to 400 per 100 000. In 2017 male Crohn's disease prevalence was 0.35% (95% confidence interval 0.34-0.36); female prevalence was 0.44% (0.43-0.45). Prevalence of inflammatory bowel disease is predicted to be 1.1% by 2025. Incidence of ulcerative colitis and Crohn's disease was 23.2 (22.8-23.6) and 14.3 (14.0-14.7) per 100 000 person-years respectively. Subjects with ulcerative colitis were more likely to develop colorectal cancer than controls (adjusted Hazard Ratio 1.40 [1.23-1.59]). Colorectal cancer rates remained stable in inflammatory bowel diseases over time. Ulcerative colitis and Crohn's disease were associated with increased risk of all-cause mortality (1.17 [1.14-1.21] and 1.42 [1.36-1.48] respectively). Conclusions: The UK prevalence of inflammatory bowel disease is greater than previous reports suggest and we predict an 11% increase in prevalence by the year 2025. Mortality risk in inflammatory bowel disease and colorectal cancer risk in ulcerative colitis are increased compared to matched controls. | 923 KING et al. Studies reporting increased mortality riskStudies reporting decrease/equivalent mortality risk Crohn's Disease Ulcerative Colitis Crohn's Disease Ulcerative ColitisAbbreviations: HR, hazard ratio; SMR, standardised mortality ratio.
BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder; however, at the time this research was conducted, no disease-modifying treatment was currently available. Medical texts often describe early-stage disease (Stages 1 and 2) as asymptomatic, but there is evidence from patients of considerable physical and emotional effects.MethodsIn-depth interviews were conducted with 80 ADPKD patients, 72 nephrologists and 85 primary care physicians (PCPs) from nine European countries to explore the experience and impact of early-stage ADPKD. Interviews were transcribed, translated and analysed centrally using thematic analysis. An additional 600 physicians completed standardised online questionnaires to investigate perceptions of symptom severity and management of early-stage ADPKD.ResultsEighty-eight per cent of patients with early-stage disease reported physical symptoms including pain, fatigue, breathlessness, weakness and a general malaise. However, 24% of nephrologists and 16% of PCPs perceived that the patients with early-stage disease did not experience any physical symptoms at all. There was a greater awareness of the emotional impact of disease, but this was still underestimated when compared with patient-reported experiences, which highlighted widespread feelings of loss, uncertainty and fear.Patients and physicians experienced frustration due to the lack of treatment options, especially in the long latent period. For many patients, the inability to affect their disease course whilst living with a diagnosis resulted in feelings of hopelessness, helplessness and depression. Physicians identified a need for improved cooperation between health-care professionals, and increased psychological support for patients.ConclusionsEarly-stage ADPKD can have a significant physical and emotional impact on patients. Whilst some physicians have an awareness of patient experience during early-stage disease, most underestimate the impact of ADPKD. Both patients and physicians are negatively affected by their inability to alter disease progression.
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