The Clinical Relevance of Manometric Esophagogastric Junction Outflow Obstruction Can Be Determined Using Rapid Drink Challenge and Solid Swallows

INTRODUCTION: Esophagogastric junction outflow obstruction (EGJOO) defined on high-resolution esophageal manometry (HRM) poses a management dilemma given marked variability in clinical manifestations. We hypothesized that findings from provocative testing (rapid drink challenge and solid swallows) could determine the clinical relevance of EGJOO. METHODS: In a retrospective cohort study, we included consecutive subjects between May 2016 and January 2020 with EGJOO. Standard HRM with 5-mL water swallows was followed by provocative testing. Barium esophagography findings were obtained. Cases with structural obstruction were separated from functional EGJOO, with the latter categorized as symptom-positive or symptom-negative. Only symptom-positive subjects were considered for achalasia-type therapies. Sensitivity and specificity for clinically relevant EGJOO during 5-mL water swallows, provocative testing, and barium were calculated. RESULTS: Of the 121 EGJOO cases, 76% had dysphagia and 25% had holdup on barium. Ninety-seven cases (84%) were defined as functional EGJOO. Symptom-positive EGJOO subjects were more likely to demonstrate abnormal motility and pressurization patterns and to reproduce symptoms during provocative testing, but not with 5-mL water swallows. Twenty-nine (30%) functional EGJOO subjects underwent achalasia-type therapy, with symptomatic response in 26 (90%). Forty-eight (49%) functional EGJOO cases were managed conservatively, with symptom remission in 78%. Although specificity was similar, provocative testing demonstrated superior sensitivity in identifying treatment responders from spontaneously remitting EGJOO (85%) compared with both 5-mL water swallows (54%; P < 0.01) and barium esophagography (54%; P = 0.02). DISCUSSION: Provocative testing during HRM is highly accurate in identifying clinically relevant EGJOO that benefits from therapy and should be routinely performed as part of the manometric protocol

The s ---> d gamma decay in and beyond the Standard Model

The New Physics sensitivity of the s ---> d gamma transition and its accessibility through hadronic processes are thoroughly investigated. Firstly, the Standard Model predictions for the direct CP-violating observables in radiative K decays are systematically improved. Besides, the magnetic contribution to epsilon prime is estimated and found subleading, even in the presence of New Physics, and a new strategy to resolve its electroweak versus QCD penguin fraction is identified. Secondly, the signatures of a series of New Physics scenarios, characterized as model-independently as possible in terms of their underlying dynamics, are investigated by combining the information from all the FCNC transitions in the s ---> d sector.Comment: 54 pages, 14 eps figure

Fenofibrate Reduces Mortality and Precludes Neurological Deficits in Survivors in Murine Model of Japanese Encephalitis Viral Infection

Background: Japanese encephalitis (JE), the most common form of viral encephalitis occurs periodically in endemic areas leading to high mortality and neurological deficits in survivors. It is caused by a flavivirus, Japanese encephalitis virus (JEV), which is transmitted to humans through mosquitoes. No effective cure exists for reducing mortality and morbidity caused by JEV infection, which is primarily due to excessive inflammatory response. Fenofibrate, a peroxisome proliferator-activated receptor-a (PPARa) agonist is known to resolve inflammation by repressing nuclear factor-kB (NF-kB) and enhancing transcription of anti-oxidant and anti-inflammatory genes. In addition, fenofibrate also up-regulates a class of proteins, cytochrome P4504Fs (Cyp4fs), which are involved in detoxification of the potent pro-inflammatory eicosanoid, leukotriene B4 (LTB4) to 20-hydroxy LTB4. Methodology/Principal Findings: The neuroprotective effect of fenofibrate was examined using in vitro (BV-2 microglial cell line) and in vivo (BALB/c mice) models of JEV infection. Mice were treated with fenofibrate for 2 or 4 days prior to JEV exposure. Pretreatment with fenofibrate for 4 but not 2 days reduced mortality by 80 % and brain LTB4 levels decreased concomitantly with the induction of Cyp4f15 and 4f18, which catalyze detoxification of LTB4 through hydroxylation. Expression of cytokines and chemokine decreased significantly as did microglial activation and replication of the JEV virus. Conclusions/Significance: Fenofibrate confers neuroprotection against Japanese encephalitis, in vivo, in mouse model o

Impact of PGL-I Seropositivity on the Protective Effect of BCG Vaccination among Leprosy Contacts: A Cohort Study

Although leprosy has become a neglected disease, it is an important cause of disability, and 250,000 new cases are still diagnosed worldwide every year. The current study was carried out in Brazil, where almost 40,000 new cases of leprosy are diagnosed every year. The study targeted contacts of leprosy patients, who are at the highest risk of contracting the disease. We studied 2,135 contacts who were diagnosed at the Leprosy Outpatient Clinic at the Oswaldo Cruz Foundation in Rio de Janeiro, RJ, Brazil, between 1987 and 2007. The presence of antibodies against a specific Mycobacterium leprae antigen (PGL-I) at the first examination and BCG vaccination status were evaluated. PGL-I-positive contacts had a higher risk of developing leprosy than PGL-I-negative contacts. Among the former, vaccinated contacts were at higher risk than unvaccinated contacts. Our results indicate that contact examination combined with PGL-I testing and BCG vaccination appears to justify the targeting of PGL-I-positive individuals for enhanced surveillance. Furthermore, it is highly recommended that PGL-I-positive contacts and contacts with a high familial bacterial index (i.e., the sum of results from index and co-prevalent cases), regardless of serological response, should be monitored. This group could be considered as a target for chemoprophylaxis

Global burden of disease due to smokeless tobacco consumption in adults : analysis of data from 113 countries

BACKGROUND: Smokeless tobacco is consumed in most countries in the world. In view of its widespread use and increasing awareness of the associated risks, there is a need for a detailed assessment of its impact on health. We present the first global estimates of the burden of disease due to consumption of smokeless tobacco by adults. METHODS: The burden attributable to smokeless tobacco use in adults was estimated as a proportion of the disability-adjusted life-years (DALYs) lost and deaths reported in the 2010 Global Burden of Disease study. We used the comparative risk assessment method, which evaluates changes in population health that result from modifying a population's exposure to a risk factor. Population exposure was extrapolated from country-specific prevalence of smokeless tobacco consumption, and changes in population health were estimated using disease-specific risk estimates (relative risks/odds ratios) associated with it. Country-specific prevalence estimates were obtained through systematically searching for all relevant studies. Disease-specific risks were estimated by conducting systematic reviews and meta-analyses based on epidemiological studies. RESULTS: We found adult smokeless tobacco consumption figures for 115 countries and estimated burden of disease figures for 113 of these countries. Our estimates indicate that in 2010, smokeless tobacco use led to 1.7 million DALYs lost and 62,283 deaths due to cancers of mouth, pharynx and oesophagus and, based on data from the benchmark 52 country INTERHEART study, 4.7 million DALYs lost and 204,309 deaths from ischaemic heart disease. Over 85 % of this burden was in South-East Asia. CONCLUSIONS: Smokeless tobacco results in considerable, potentially preventable, global morbidity and mortality from cancer; estimates in relation to ischaemic heart disease need to be interpreted with more caution, but nonetheless suggest that the likely burden of disease is also substantial. The World Health Organization needs to consider incorporating regulation of smokeless tobacco into its Framework Convention for Tobacco Control

Re-Patterning Sleep Architecture in Drosophila through Gustatory Perception and Nutritional Quality

Organisms perceive changes in their dietary environment and enact a suite of behavioral and metabolic adaptations that can impact motivational behavior, disease resistance, and longevity. However, the precise nature and mechanism of these dietary responses is not known. We have uncovered a novel link between dietary factors and sleep behavior in Drosophila melanogaster. Dietary sugar rapidly altered sleep behavior by modulating the number of sleep episodes during both the light and dark phase of the circadian period, independent of an intact circadian rhythm and without affecting total sleep, latency to sleep, or waking activity. The effect of sugar on sleep episode number was consistent with a change in arousal threshold for waking. Dietary protein had no significant effect on sleep or wakefulness. Gustatory perception of sugar was necessary and sufficient to increase the number of sleep episodes, and this effect was blocked by activation of bitter-sensing neurons. Further addition of sugar to the diet blocked the effects of sweet gustatory perception through a gustatory-independent mechanism. However, gustatory perception was not required for diet-induced fat accumulation, indicating that sleep and energy storage are mechanistically separable. We propose a two-component model where gustatory and metabolic cues interact to regulate sleep architecture in response to the quantity of sugar available from dietary sources. Reduced arousal threshold in response to low dietary availability may have evolved to provide increased responsiveness to cues associated with alternative nutrient-dense feeding sites. These results provide evidence that gustatory perception can alter arousal thresholds for sleep behavior in response to dietary cues and provide a mechanism by which organisms tune their behavior and physiology to environmental cues