Evolution of treatment targets in Crohn’s disease

Crohn’s disease is a chronic relapsing and remitting inflammatory disorder of the gastrointestinal tract, associated with significantly morbidity due to both symptoms and complications that have a considerable detrimental impact on a patient’s quality of life. An early treat to target approach with disease modifying agents has been shown to significantly improve long term outcomes, demonstrated by a number of therapeutic targets in a number of modalities. This review will outline the current treatment targets and measures of disease burden in Crohn’s disease

"To Aid Their Rebel Friends": Politics and Treason in the Civil War North

In "To Aid Their Rebel Friends" I argue that Civil War-era politicians relied on meanings of treason from old English law and Revolutionary-era America to broaden the definition of treason beyond the narrow definition found in the Constitution. In doing so, they gave new meaning to words and phrases in the Constitution that had been dormant for many years. Treason is the only crime defined in the U.S. Constitution: "Treason against the United States, shall consist only in levying War against them, or in adhering to their Enemies, giving them Aid and Comfort." The next sentence states that treason must be an "overt Act," thus precluding judges or politicians from declaring that conspiracy or words might be deemed treason. In defining treason narrowly the Framers hoped to depoliticize a crime that for centuries had been political in nature. In early modern England kings could define treason however they chose and force judges to convict the accused, simply to eliminate political opposition. Moreover, since the fourteenth century it was a treasonable offence to imagine or compass the king's death. The Founders hoped to avoid such occurrences on American soil. Despite the Founders' precaution of carefully defining treason in the nation's fundamental law, the Civil War transformed how treason was understood in American legal and political culture. The definition of treason broadened to include more than just overt acts of war. Included in its meaning were also disloyal or treasonous words. Sedition was punished, though not always as a defined crime. Speech codes were enforced in several northern states, and loyalty oaths were required at all levels of government and in nearly every jurisdiction. Violations of these laws, or refusals to take prescribed oaths, opened up northern citizens to charges of treason and disloyalty. In essence, the line between words and deeds blurred so that someone might be considered a traitor for speaking "traitorously" or for harboring "disloyal" sentiments. Beyond looking at the federal level, this dissertation also examines how understandings of treason broadened at the state and local levels, something that no scholar has yet attempted to do

Modelling the impact of local reactive school closures on critical care provision during an influenza pandemic

Despite the fact that the 2009 H1N1 pandemic influenza strain was less severe than had been feared, both seasonal epidemics of influenza-like-illness and future influenza pandemics have the potential to place a serious burden on health services. The closure of schools has been postulated as a means of reducing transmission between children and hence reducing the number of cases at the peak of an epidemic; this is supported by the marked reduction in cases during school holidays observed across the world during the 2009 pandemic. However, a national policy of long-duration school closures could have severe economic costs. Reactive short-duration closure of schools in regions where health services are close to capacity offers a potential compromise, but it is unclear over what spatial scale and time frame closures would need to be made to be effective. Here, using detailed geographical information for England, we assess how localized school closures could alleviate the burden on hospital intensive care units (ICUs) that are reaching capacity. We show that, for a range of epidemiologically plausible assumptions, considerable local coordination of school closures is needed to achieve a substantial reduction in the number of hospitals where capacity is exceeded at the peak of the epidemic. The heterogeneity in demand per hospital ICU bed means that even widespread school closures are unlikely to have an impact on whether demand will exceed capacity for many hospitals. These results support the UK decision not to use localized school closures as a control mechanism, but have far wider international public-health implications. The spatial heterogeneities in both population density and hospital capacity that give rise to our results exist in many developed countries, while our model assumptions are sufficiently general to cover a wide range of pathogens. This leads us to believe that when a pandemic has severe implications for ICU capacity, only widespread school closures (with their associated costs and organizational challenges) are sufficient to mitigate the burden on the worst-affected hospitals

Entanglement Creation Using Quantum Interrogation

We present some applications of high efficiency quantum interrogation ("interaction free measurement") for the creation of entangled states of separate atoms and of separate photons. The quantum interrogation of a quantum object in a superposition of object-in and object-out leaves the object and probe in an entangled state. The probe can then be further entangled with other objects in subsequent quantum interrogations. By then projecting out those cases were the probe is left in a particular final state, the quantum objects can themselves be left in various entangled states. In this way we show how to generate two-, three-, and higher qubit entanglement between atoms and between photons. The effect of finite efficiency for the quantum interrogation is delineated for the various schemes.Comment: 7 pages, 13 figures, Submitted to PR

Multiple imputation of covariates by fully conditional specification: Accommodating the substantive model.

Missing covariate data commonly occur in epidemiological and clinical research, and are often dealt with using multiple imputation. Imputation of partially observed covariates is complicated if the substantive model is non-linear (e.g. Cox proportional hazards model), or contains non-linear (e.g. squared) or interaction terms, and standard software implementations of multiple imputation may impute covariates from models that are incompatible with such substantive models. We show how imputation by fully conditional specification, a popular approach for performing multiple imputation, can be modified so that covariates are imputed from models which are compatible with the substantive model. We investigate through simulation the performance of this proposal, and compare it with existing approaches. Simulation results suggest our proposal gives consistent estimates for a range of common substantive models, including models which contain non-linear covariate effects or interactions, provided data are missing at random and the assumed imputation models are correctly specified and mutually compatible. Stata software implementing the approach is freely available

Hypertension in mice lacking 11beta-hydroxysteroid dehydrogenase type 2

Deficiency of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in humans leads to the syndrome of apparent mineralocorticoid excess (SAME), in which cortisol illicitly occupies mineralocorticoid receptors, causing sodium retention, hypokalemia, and hypertension. However, the disorder is usually incompletely corrected by suppression of cortisol, suggesting additional and irreversible changes, perhaps in the kidney. To examine this further, we produced mice with targeted disruption of the 11β-HSD2 gene. Homozygous mutant mice (11β-HSD2(–/–)) appear normal at birth, but ∼50% show motor weakness and die within 48 hours. Both male and female survivors are fertile but exhibit hypokalemia, hypotonic polyuria, and apparent mineralocorticoid activity of corticosterone. Young adult 11β-HSD2(–/–) mice are markedly hypertensive, with a mean arterial blood pressure of 146 ± 2 mmHg, compared with 121 ± 2 mmHg in wild-type controls and 114 ± 4 mmHg in heterozygotes. The epithelium of the distal tubule of the nephron shows striking hypertrophy and hyperplasia. These histological changes do not readily reverse with mineralocorticoid receptor antagonism in adulthood. Thus, 11β-HSD2(–/–) mice demonstrate the major features of SAME, providing a unique rodent model to study the molecular mechanisms of kidney resetting leading to hypertension. J. Clin. Invest. 103:683–689 (1999

EXPOSURE TIME OF ORAL RABIES VACCINE BAITS RELATIVE TO BAITING DENSITY AND RACCOON POPULATION DENSITY

Oral rabies vaccination (ORV) baiting programs for control of raccoon (Procyon lotor) rabies in the USA have been conducted or are in progress in eight states east of the Mississippi River. However, data specific to the relationship between raccoon population density and the minimum density of baits necessary to significantly elevate rabies immunity are few. We used the 22-km2 US National Aeronautics and Space Administration Plum Brook Station (PBS) in Erie County, Ohio, USA, to evaluate the period of exposure for placebo vaccine baits placed at a density of 75 baits/km2 relative to raccoon population density. Our objectives were to 1) estimate raccoon population density within the fragmented forest, old-field, and industrial landscape at PBS; and 2) quantify the time that placebo, Merial RABORAL V-RG* vaccine baits were available to raccoons. From August through November 2002 we surveyed raccoon use of PBS along 19.3 km of paved-road transects by using a forward-looking infrared camera mounted inside a vehicle. We used Distance 3.5 software to calculate probability of detection function by which we estimated raccoon population density from transect data. Estimated population density on PBS decreased from August (33.4 raccoons/km2) through November (13.6 raccoons/km2), yielding a monthly mean of 24.5 raccoons/km2. We also quantified exposure time for ORV baits placed by hand on five 1-km2 grids on PBS from September through October. An average 82.7% (SD=4.6) of baits were removed within 1 wk of placement. Given raccoon population density, estimates of bait removal and sachet condition, and assuming 22.9% nontarget take, the baiting density of 75/ km\u27 yielded an average of 3.3 baits consumed per raccoon anti the sachet perforated

EXPOSURE TIME OF ORAL RABIES VACCINE BAITS RELATIVE TO BAITING DENSITY AND RACCOON POPULATION DENSITY

Oral rabies vaccination (ORV) baiting programs for control of raccoon (Procyon lotor) rabies in the USA have been conducted or are in progress in eight states east of the Mississippi River. However, data specific to the relationship between raccoon population density and the minimum density of baits necessary to significantly elevate rabies immunity are few. We used the 22-km2 US National Aeronautics and Space Administration Plum Brook Station (PBS) in Erie County, Ohio, USA, to evaluate the period of exposure for placebo vaccine baits placed at a density of 75 baits/km2 relative to raccoon population density. Our objectives were to 1) estimate raccoon population density within the fragmented forest, old-field, and industrial landscape at PBS; and 2) quantify the time that placebo, Merial RABORAL V-RG* vaccine baits were available to raccoons. From August through November 2002 we surveyed raccoon use of PBS along 19.3 km of paved-road transects by using a forward-looking infrared camera mounted inside a vehicle. We used Distance 3.5 software to calculate probability of detection function by which we estimated raccoon population density from transect data. Estimated population density on PBS decreased from August (33.4 raccoons/km2) through November (13.6 raccoons/km2), yielding a monthly mean of 24.5 raccoons/km2. We also quantified exposure time for ORV baits placed by hand on five 1-km2 grids on PBS from September through October. An average 82.7% (SD=4.6) of baits were removed within 1 wk of placement. Given raccoon population density, estimates of bait removal and sachet condition, and assuming 22.9% nontarget take, the baiting density of 75/ km\u27 yielded an average of 3.3 baits consumed per raccoon anti the sachet perforated