Coupling between waveguides and microresonators: the local approach.

Coupling between optical microresonators and waveguides is a critical characteristic of resonant photonic devices that has complex behavior that is not well understood. When the characteristic variation length of the microresonator modes is much larger than the waveguide width, local coupling parameters emerge that are independent of the resonator mode distributions and offer a simplified description of coupling behavior. We develop a robust numerical-fitting-based methodology for experimental determination of the local coupling parameters in all coupling regimes and demonstrate their characterization along a microfiber waveguide coupled to an elongated bottle microresonator.

Pruritus secondary to primary biliary cholangitis: a review of the pathophysiology and management with phototherapy.

BACKGROUND: Primary biliary cholangitis (PBC) is an autoimmune hepatobiliary disorder characterized by destruction of liver bile ducts leading to intrahepatic cholestasis. It causes intractable pruritus for which ultraviolet (UV)B phototherapy is an experimental treatment when alternative therapies fail. The pathophysiology of cholestatic itch and the mechanism of action of narrowband UVB in this condition remains poorly understood. OBJECTIVES: To summarize the current literature and propose testable hypotheses for the mechanism of action of phototherapy in attenuating itch. METHODS: A focused PubMed search for articles relating to the pathogenesis of itch in cholestatic disease was performed. A total of 3855 articles were screened and 50 were found suitable for literature review. Evidence from this literature review was combined with author expertise in the area. RESULTS: Formulated hypotheses focus on the role of bile salts, autotaxin and specific receptors including G-protein-coupled bile acid receptor, Gpbar1 (also known as TGR5) and the nuclear transcription factor farnesoid X receptor. CONCLUSIONS: Several testable mechanisms through which phototherapy may exert its effects are discussed in this review. The next steps are to carry out an objective assessment of the efficacy of phototherapy in cholestatic pruritus, gain further knowledge on the underlying pathways, and subsequently trial its use against current licensed therapies. Such studies could lead to increased mechanistic understanding, identification of novel therapeutic targets and the potential to refine phototherapy protocols, leading to improved control of itch and quality of life in patients with PBC. What's already known about this topic? Primary biliary cholangitis (PBC) is frequently associated with intractable pruritus for which current treatment options are often unsuccessful. Phototherapy is used as an experimental treatment for PBC-associated pruritus when alternative better-studied treatments fail. What does this study add? This study reviews the current literature on the pathophysiology and management of cholestatic pruritus, an area which remains poorly understood. We propose testable hypotheses of the mechanisms behind the attenuation of cholestatic pruritus with phototherapy.

Molecular mechanisms for anthelmintic resistance in strongyle nematode parasites of veterinary importance.

Veterinarians rely on a relatively limited spectrum of anthelmintic agents to control nematode parasites in domestic animals. Unfortunately, anthelmintic resistance has been an emerging problem in veterinary medicine. In particular, resistance has emerged among the strongyles, a group of gastrointestinal nematodes that infect a variety of hosts that range from large herbivores to small companion animals. Over the last several decades, a great deal of research effort has been directed toward developing an understanding of the mechanisms conferring resistance against the three major groups of anthelmintics: macrocyclic lactones, benzimidazoles, and nicotinic agonists. Our understanding of anthelmintic resistance has been largely formed by determining the mechanism of action for each drug class and then evaluating drug-resistant nematode isolates for mutations or differences in expression of target genes. More recently, drug efflux pumps have been recognized for their potential contribution to anthelmintic resistance. In this mini-review, we summarize the evidence for mechanisms of resistance in strongyle nematodes.

The inter-relationship of symptom severity and quality of life in 2055 patients with primary biliary cholangitis.

BACKGROUND: Age at presentation with primary biliary cholangitis (PBC) is associated with differential response to ursodeoxycholic acid (UDCA) therapy. Younger-presenting patients are less likely to respond to treatment and more likely to need transplant or die from the disease. PBC has a complex impact on quality of life (QoL), with systemic symptoms often having significant impact. AIM: To explain the impact of age at presentation on perceived QoL and the inter-related symptoms which impact upon it. METHODS: Using the UK-PBC cohort, symptoms were assessed using the PBC-40 and other validated tools. Data were available on 2055 patients. RESULTS: Of the 1990 patients reporting a global PBC-QoL score, 66% reported good/neutral scores and 34% reported poor scores. Each 10-year increase in age at presentation was associated with a 14% decrease in risk of poor perceived QoL (OR = 0.86, 95% CI: 0.75-0.98, P < 0.05). All symptom domains were similarly age-associated (P < 0.01). Social dysfunction was the symptom factor with the greatest impact on QoL. Median (interquartile range) PBC-40 social scores for patients with good perceived QoL were 18 (14-23) compared with 34 (29-39) for those with poor QoL. CONCLUSION: The majority of patients with primary biliary cholangitis do not feel their QoL is impaired, although impairment is reported by a sizeable minority. Age at presentation is associated with impact on perceived QoL and the symptoms impairing it, with younger patients being more affected. Social dysfunction makes the greatest contribution to QoL impairment, and it should be targeted in trials aimed at improving life quality.

Early primary biliary cholangitis is characterised by brain abnormalities on cerebral magnetic resonance imaging.

BACKGROUND: Brain change can occur in primary biliary cholangitis (PBC), potentially as a result of cholestatic and/or inflammatory processes. This change is linked to systemic symptoms of fatigue and cognitive impairment. AIM: To identify whether brain change occurs early in PBC. If the change develops early and is progressive, it may explain the difficulty in treating these symptoms. METHODS: Early disease brain change was explored in 13 patients with newly diagnosed biopsy-proven precirrhotic PBC using magnetisation transfer, diffusion-weighted imaging and 1 H magnetic resonance spectroscopy. Results were compared to 17 healthy volunteers. RESULTS: Cerebral magnetisation transfer ratios were reduced in early PBC, compared to healthy volunteers, in the thalamus, putamen and head of caudate with no greater reduction in patients with greater symptom severity. Mean apparent diffusion coefficients were increased in the thalamus only. No 1 H magnetic resonance spectroscopy abnormalities were seen. Serum manganese levels were elevated in all PBC patients, but no relationship was seen with imaging or symptom parameters. There were no correlations between neuroimaging data, laboratory data, symptom severity scores or age. CONCLUSIONS: This is the first study to be performed in this precirrhotic patient population, and we have highlighted that neuroimaging changes are present at a much earlier stage than previously demonstrated. The neuroimaging abnormalities suggest that the brain changes seen in PBC occur early in the pathological process, even before significant liver damage has occurred. If such changes are linked to symptom pathogenesis, this could have important implications for the timing of second-line-therapy use.

Nanofiber-segment ring resonator.

We describe a fiber ring resonator comprised of a relatively long loop of standard single-mode fiber with a short nanofiber segment. The evanescent mode of the nanofiber segment allows the cavity-enhanced field to interact with atoms in close proximity to the nanofiber surface. We report on an experiment using a warm atomic vapor and low-finesse cavity, and briefly discuss the potential for reaching the strong coupling regime of cavity QED by using trapped atoms and a high-finesse cavity of this kind.

The safety and efficacy of nasobiliary drainage in the treatment of refractory cholestatic pruritus: a multicentre European study.

BACKGROUND: Pruritus is a common symptom associated with cholestatic liver diseases. To date only small single centre case series have suggested efficacy of nasobiliary drainage in relieving cholestatic pruritus. AIM: To perform a multicentre study to evaluate the safety and efficacy of nasobiliary drainage in cholestatic pruritus. METHODS: This was a retrospective study of all patients treated with nasobiliary drainage for refractory cholestatic pruritus between 2006 and 2015 at five European centres. Pruritus was quantified using a visual analogue scale (VAS) and liver enzymes, serum bilirubin and total serum bile salts (TBS) were measured before (pre-NBD) and after nasobiliary drainage (post-NBD). We analysed the duration of treatment response and associated complications. RESULTS: In total, 27 patients (59% females) underwent 29 nasobiliary drainage procedures. The median duration of NBD was 7 days. NBD decreased pruritus in 89.6% of cases (VAS from 10.0 to 0.3, P < 0.0001). The median percentage decline in pruritus VAS was 94% and 33% of patients were free of pruritus within 24 h of starting drainage. The duration of treatment response was independent of duration of drainage (P = 0.12) and bile output. Significant improvements were seen in the median levels of serum alkaline phosphatase (P = 0.001) and serum bilirubin (P = 0.03) but not in serum TBS (P = 0.07). Mild post-endoscopic retrograde cholangiopancreatography pancreatitis (31%) was the most frequent complication. CONCLUSIONS: Nasobiliary drainage is effective in relieving cholestatic pruritus in most patients and has favourable effect on biomarkers of cholestasis. Nasobiliary drainage may be associated with high risk of adverse events, especially pancreatitis. Prospective studies are needed to confirm our findings.

Revised Recommendations of the Consortium of MS Centers Task Force for a Standardized MRI Protocol and Clinical Guidelines for the Diagnosis and Follow-Up of Multiple Sclerosis.

An international group of neurologists and radiologists developed revised guidelines for standardized brain and spinal cord MR imaging for the diagnosis and follow-up of MS. A brain MR imaging with gadolinium is recommended for the diagnosis of MS. A spinal cord MR imaging is recommended if the brain MR imaging is nondiagnostic or if the presenting symptoms are at the level of the spinal cord. A follow-up brain MR imaging with gadolinium is recommended to demonstrate dissemination in time and ongoing clinically silent disease activity while on treatment, to evaluate unexpected clinical worsening, to re-assess the original diagnosis, and as a new baseline before starting or modifying therapy. A routine brain MR imaging should be considered every 6 months to 2 years for all patients with relapsing MS. The brain MR imaging protocol includes 3D T1-weighted, 3D T2-FLAIR, 3D T2-weighted, post-single-dose gadolinium-enhanced T1-weighted sequences, and a DWI sequence. The progressive multifocal leukoencephalopathy surveillance protocol includes FLAIR and DWI sequences only. The spinal cord MR imaging protocol includes sagittal T1-weighted and proton attenuation, STIR or phase-sensitive inversion recovery, axial T2- or T2*-weighted imaging through suspicious lesions, and, in some cases, postcontrast gadolinium-enhanced T1-weighted imaging. The clinical question being addressed should be provided in the requisition for the MR imaging. The radiology report should be descriptive, with results referenced to previous studies. MR imaging studies should be permanently retained and available. The current revision incorporates new clinical information and imaging techniques that have become more available.

Public health decisions: actions and consequences.

The goal of public health is to promote the best possible health for the whole population. Public health issues are numerous and can be unbelievably complex in form, scope, and possible consequence. Most public health decisions involve assessing several different options, weighing the respective benefits and risks of those options, and making difficult decisions that hopefully provide the greatest benefit to the affected populations. Many risk management decisions involve a variety of societal factors which modify risk assessment choices. The purpose of this paper is to point out difficulties in making decisions that impact public health. The intent of such decisions is to improve public health, but as illustrated in the paper, there can be unintended adverse consequences. Such unplanned issues require continued attention and efforts for responsible officials in the protection of environmental public health. This article presents examples of such events, when in the past, it was necessary to assess and regulate a number of potentially hazardous chemicals commonly used as insecticides, gasoline additives, and wood preservatives.

Biliary epithelial senescence and plasticity in acute cellular rejection.

Biliary epithelial cells (BEC) are important targets in some liver diseases, including acute allograft rejection. Although some injured BEC die, many can survive in function compromised states of senescence or phenotypic de-differentiation. This study was performed to examine changes in the phenotype of BEC during acute liver allograft rejection and the mechanism driving these changes. Liver allograft sections showed a positive correlation (p < 0.0013) between increasing T cell mediated acute rejection and the number of BEC expressing the senescence marker p21(WAF1/Cip) or the mesenchymal marker S100A4. This was modeled in vitro by examination of primary or immortalized BEC after acute oxidative stress. During the first 48 h, the expression of p21(WAF1/Cip) was increased transiently before returning to baseline. After this time BEC showed increased expression of mesenchymal proteins with a decrease in epithelial markers. Analysis of TGF-ß expression at mRNA and protein levels also showed a rapid increase in TGF-ß2 (p < 0.006) following oxidative stress. The epithelial de-differentiation observed in vitro was abrogated by pharmacological blockade of the ALK-5 component of the TGF-ß receptor. These data suggest that stress induced production of TGF-ß2 by BEC can modify liver allograft function by enhancing the de-differentiation of local epithelial cells.

Effect of systemic antibiotics and topical chlorhexidine on meticillin-resistant Staphylococcus aureus carriage in intensive care unit patients.

Antibiotics and antiseptics have the potential to influence carriage and transmission of meticillin-resistant Staphylococcus aureus (MRSA), although effects are likely to be complex, particularly in a setting where multiple agents are used. Here admission and weekly MRSA screens and daily antibiotic and antiseptic prescribing data from 544 MRSA carriers on an intensive care unit (ICU) are used to determine the effect of these agents on short-term within-host MRSA carriage dynamics. Longitudinal data were analysed using Markov models allowing patients to move between two states: MRSA positive (detectable MRSA carriage) and MRSA negative (no detectable carriage). The effect of concurrent systemic antibiotic and topical chlorhexidine (CHX) on movement between these states was assessed. CHX targeted to MRSA screen carriage sites increased transition from culture positive to negative and there was also weaker evidence that it decreased subsequent transition from negative back to positive. In contrast, there was only weak and inconsistent evidence that any antibiotic influenced transition in either direction. For example, whereas univariate analysis found quinolones to be strongly associated with both increased risk of losing and then reacquiring MRSA carriage over time intervals of one day, no effect was seen with weekly models. Similar studies are required to determine the generalisability of these findings.

Echocardiographic detection of pulmonary hypertension in extremely low birth weight infants with bronchopulmonary dysplasia requiring prolonged positive pressure ventilation.

OBJECTIVE: The goal of this study was to delineate the epidemiology of echocardiographically diagnosed pulmonary hypertension (PH) in extremely low birth weight (ELBW) infants with bronchopulmonary dysplasia (BPD) requiring prolonged positive pressure ventilation (PPV), and to determine the independent relationship between PH and mortality in these patients. STUDY DESIGN: Our retrospective cohort included ELBW infants, with BPD requiring prolonged PPV, hospitalized in Cincinnati, Ohio during 2003-2009, as recorded in the National Institute of Child Health and Human Development Neonatal Research Network Database. Following chart review, a logistic regression model was constructed to understand the contribution of PH to mortality in infants with BPD requiring prolonged PPV. RESULT: We identified 216 patients (19%) with BPD requiring prolonged PPV among 1156 ELBW infants. Of these patients, 41% received echocardiography after 4 weeks of life, with 37% showing evidence of PH. Logistic regression analysis demonstrated that infants with BPD requiring prolonged PPV, with PH detectable by echocardiogram, were four times more likely to die (adjusted odds ratio): 4.6, 95% confidence interval: 1.3-16.5) when compared with infants with BPD requiring prolonged PPV without echocardiographic evidence of PH. CONCLUSION: Pulmonary hypertension appears to be an important, independent determinant of death in infants with BPD requiring prolonged PPV.

Fatigue severity remains stable over time and independently associated with orthostatic symptoms in chronic fatigue syndrome: a longitudinal study.

OBJECTIVES: to examine fatigue variability over time in chronic fatigue syndrome (CFS) and the effect of other symptoms on its predictability. DESIGN: longitudinal cohort study of patients with CFS (Fukuda criteria). SETTING: specialist CFS clinical service. SUBJECTS: phase 1: 100 patients who participated in a study of CFS symptoms in 2005 were revisited in 2009. Phase 2: 25 patients completed fatigue diaries to address intra- and inter-day variability in perceived fatigue. MAIN OUTCOME MEASURES: phase 1: subjects completed fatigue impact scale (FIS), Epworth sleepiness scale (ESS), orthostatic grading scale (OGS) and hospital anxiety and depression scale (HADS). Changes in variables represented the differences between 2005 and 2009. Phase 2: subjects rated fatigue on a scale of 0 (no fatigue) to 10 (severe fatigue) four times a day for 5 weeks. RESULTS: symptom assessment tools were available in both 2005 and 2009 for 74% of patients. FIS and HADS depression (HAD-D) and anxiety (HAD-A) scores significantly improved during follow-up whereas ESS and OGS remained stable. FIS improved in 29/74 (39%) subjects, and by ≥ 10 points in 19 (26%). FIS worsened by ≥ 10 points in 33/74 (45%) subjects. On multivariate analysis, independent predictors of current fatigue (FIS in 2009) were FIS in 2005, HAD-D in 2009, OGS in 2009 and change in HAD-A. Reported fatigue was stable from week to week and from day to day. Patients reported higher fatigue in the morning (mean ± SD; 6.4 ± 2), becoming significantly lower at lunchtime (6.2 ± 2; P < 0.05) and increasing again to 7 ± 2 at bedtime. CONCLUSIONS: current fatigue is independently associated with current autonomic symptom burden, current depression and change in anxiety during follow-up. These findings have implications for targeted symptom management in CFS.

Abnormalities in pH handling by peripheral muscle and potential regulation by the autonomic nervous system in chronic fatigue syndrome.

OBJECTIVES: To examine muscle acid handling following exercise in chronic fatigue syndrome (CFS/ME) and the relationship with autonomic dysfunction. DESIGN: Observational study. SETTING: Regional fatigue service. SUBJECTS & INTERVENTIONS: Chronic fatigue syndrome (n = 16) and age and sex matched normal controls (n = 8) underwent phosphorus magnetic resonance spectroscopy (MRS) to evaluate pH handling during exercise. Subjects performed plantar flexion at fixed 35% load maximum voluntary contraction. Heart rate variability was performed during 10 min supine rest using digital photophlethysmography as a measure of autonomic function. RESULTS: Compared to normal controls, the CFS/ME group had significant suppression of proton efflux both immediately postexercise (CFS: 1.1 +/- 0.5 mmol L(-1) min(-1) vs. normal: 3.6 +/- 1.5 mmol L(-1) min(-1), P < 0.001) and maximally (CFS: 2.7 +/- 3.4 mmol L(-1) min(-1) vs. control: 3.8 +/- 1.6 mmol L(-1) min(-1), P < 0.05). Furthermore, the time taken to reach maximum proton efflux was significantly prolonged in patients (CFS: 25.6 +/- 36.1 s vs. normal: 3.8 +/- 5.2 s, P < 0.05). In controls the rate of maximum proton efflux showed a strong inverse correlation with nadir muscle pH following exercise (r(2) = 0.6; P < 0.01). In CFS patients, in contrast, this significant normal relationship was lost (r(2) = 0.003; P = ns). In normal individuals, the maximum proton efflux following exercise were closely correlated with total heart rate variability (r(2) = 0.7; P = 0.007) this relationship was lost in CFS/ME patients (r(2) < 0.001; P = ns). CONCLUSION: Patients with CFS/ME have abnormalities in recovery of intramuscular pH following standardised exercise degree of which is related to autonomic dysfunction. This study identifies a novel biological abnormality in patients with CFS/ME which is potentially open to modification.

Primary biliary cirrhosis is associated with falls and significant fall related injury.

BACKGROUND: Osteoporosis and autonomic dysfunction are prevalent in the autoimmune liver disease primary biliary cirrhosis (PBC). Postural hypotension is one consequence of autonomic dysfunction and is a recognized risk factor for falls, which, alongside osteoporosis could lead to significant injury and fractures. AIM: To determine the prevalence and sequelae of falls in PBC and to identify modifiable risk factors. DESIGN: Cross-sectional, geographical, population census of PBC and two control groups: primary sclerosing cholangitis and a community dwelling population. Multidisciplinary falls assessment of a representative group of PBC. METHODS: Symptom assessment tools, completed by the three cohorts, determined the prevalence of falls, injuries and associated symptoms. Multidisciplinary assessments, adhering to NICE guidelines, identified modifiable fall associations. RESULTS: Significantly more of the PBC population had fallen (72% P < 0.001) than both control groups. Fifty-five percent had fallen in the last year (P < 0.001), and 22% more than once in the last year (P < 0.01). Seventy percent of PBC fallers were injured, 27% fractured a bone and 19% were admitted to hospital, all significantly more common than controls. Postural dizziness was significantly worse in fallers (P < 0.001), as were balance (P < 0.001) and lower limb strength (P = 0.002). Lower limb strength was independently associated with number of falls in previous year (beta = 0.184, P < 0.001). CONCLUSION: Falls and resultant injury are prevalent in PBC and more common than previously recognized. Addressing postural dizziness, poor balance and lower limb weakness using a multidisciplinary approach has the potential to reduce falls, morbidity and mortality and as a result improve quality of life.

Perceived fatigue is comparable between different disease groups.

BACKGROUND: Studies have established that levels of fatigue vary between different patient groups. It is less clear whether the nature, as opposed to severity of fatigue differs between groups. OBJECTIVE: To examine descriptions of fatigue by patients with a range of chronic diseases and determine the relationship between symptom domains. DESIGN: Retrospective review of Fatigue Impact Scale (FIS) data. SETTING: Fatigue Research Group. PARTICIPANTS: Six hundred subjects in five chronic disease groups and one (n = 45) normal control group. MAIN OUTCOME MEASURES: Statistical analysis was performed to assess the effect of increasing fatigue and the overlap of FIS domain scores between disease groups by calculation of geometric means as proportions summed to 1 in each FIS domains, whilst controlling for total score. RESULTS: Those with lower scores exhibit relatively higher physical scores than patients with higher total scores. In contrast, as total score increases, so does the proportion accounted for by the cognitive and psychosocial scores. This was not related to a threshold effect as the maximum total score of 40 in the physical domain was only achieved in three patients (<1%). Average domain proportions between patient groups did not vary to any degree among physical (0.30-0.39), cognitive (0.15-0.23) and psychosocial (0.42-0.47) domain proportions of the patient groups. CONCLUSION: Perceived fatigue is similar between patient groups. Increasing scores were not related to simply reaching the maximum threshold in the physical domain. Studies have confirmed a positive-structured approach to symptom management in one fatigue-associated chronic disease, primary biliary cirrhosis, leads to significant improvements in quality of life. We suggest that, with a similar approach, the same might be true in other chronic diseases where moderate fatigue is a significant problem.

Detection of polycyclic aromatic hydrocarbons in the shed skins of corn snakes (Elaphe guttata).

Previous work has shown that organochlorine compounds, including chlordane, lindane and polychlorinated biphenyls, and heavy metals, including lead, mercury and cadmium, are readily detected in the shed skins of snakes dosed with these toxicants. This suggested the shed skins may have broad utility as a non-lethal biomarker tissue for environmental contamination. In the present study, two polycyclic aromatic hydrocarbons (PAHs), benzo[a]pyrene (B[a]P) and 3-methylcholanthrene (3-MC), were similarly studied, as representatives of a third major pollutant category of environmental concern. Both compounds were again readily detected in shed snake skins. These collective results suggest considerable environmental contamination information might be obtained from the evaluation of field-collected shed skins. An advantage of such evaluation is that capture, handling or sacrifice of the live animals is not required.

Activation of peripheral blood monocytes results in more robust production of IL-10 in neonatal foals compared to adult horses.

Foals are particularly vulnerable to infection by Rhodococcus equi during the first 2 weeks of life whereas mature horses are not. While an innate immunodeficiency likely accounts for this clinically relevant vulnerability, the factors that contribute to infection by R. equi have not been fully elucidated. In this study, we demonstrate that cells of the monocyte lineage, including monocytes, macrophages, and dendritic cells, that have been activated with LPS and IFN-gamma, respond with a statistically significant, greater amount of cytokine mRNA production of IL-10, IL-12p35, and IL-12p40 than unstimulated control cells. Interestingly, activation of neonatal cells resulted in a twofold log increase in baseline cytokine mRNA expression of IL-10 compared with adult cells. In contrast, no significant differences in mean cytokine mRNA expression of IL-12p35 and IL-12p40 were detected, suggesting that the defect in chromosomal remodeling that prevents IL-12p35 gene transcription as a cause for decreased IL-12 synthesis in human neonates is not a likely occurrence in equine neonates. Collectively, these differences indicate that in vivo activation of equine cells of the monocyte lineage may result in different autocrine and paracrine cellular responses that vary according to age, with potential impact on regulation of adaptive and innate immune responses.