Contact complete integrability

Complete integrability in a symplectic setting means the existence of a Lagrangian foliation leaf-wise preserved by the dynamics. In the paper we describe complete integrability in a contact set-up as a more subtle structure: a flag of two foliations, Legendrian and co-Legendrian, and a holonomy-invariant transverse measure of the former in the latter. This turns out to be equivalent to the existence of a canonical $\R\ltimes \R^{n-1}$ structure on the leaves of the co-Legendrian foliation. Further, the above structure implies the existence of $n$ contact fields preserving a special contact 1-form, thus providing the geometric framework and establishing equivalence with previously known definitions of contact integrability. We also show that contact completely integrable systems are solvable in quadratures. We present an example of contact complete integrability: the billiard system inside an ellipsoid in pseudo-Euclidean space, restricted to the space of oriented null geodesics. We describe a surprising acceleration mechanism for closed light-like billiard trajectories

Choice of first-line antiretroviral therapy regimen and treatment outcomes for HIV in a middle income compared to a high income country: a cohort study

BACKGROUND: The range of combination antiretroviral therapy (cART) regimens available in many middle-income countries differs from those suggested in international HIV treatment guidelines. We compared first-line cART regimens, timing of initiation and treatment outcomes in a middle income setting (HIV Centre, Belgrade, Serbia - HCB) with a high-income country (Royal Free London Hospital, UK - RFH). METHODS: All antiretroviral-naïve HIV-positive individuals from HCB and RFH starting cART between 2003 and 2012 were included. 12-month viral load and CD4 count responses were compared, considering the first available measurement 12-24 months post-cART. The percentage that had made an antiretroviral switch for any reason, or for toxicity and the percentage that had died by 36 months (the latest time at which sufficient numbers remained under follow-up) were investigated using standard survival methods. RESULTS: 361/597 (61 %) of individuals initiating cART at HCB had a prior AIDS diagnosis, compared to 337/1763 (19 %) at RFH. Median pre-ART CD4 counts were 177 and 238 cells/mm(3) respectively (p < 0.0001). The most frequently prescribed antiretrovirals were zidovudine with lamivudine (149; 25 %) and efavirenz [329, 55 %] at HCB and emtricitabine with tenofovir (899; 51 %) and efavirenz [681, 39 %] at RFH. At HCB, a median of 2 CD4 count measurements in the first year of cART were taken, compared to 5 at RFH (p < 0.0001). Median (IQR) CD4 cell increase after 12 months was +211 (+86, +359) and +212 (+105, +318) respectively. 287 (48 %) individuals from HCB and 1452 (82 %) from RFH had an available viral load measurement, of which 271 (94 %) and 1280 (88 %) were <400 copies/mL (p < 0.0001). After 36 months, comparable percentages had made at least one antiretroviral switch (77 % HCB vs. 78 % RFH; p = 0.23). However, switches for toxicity/patient choice were more common at RFH. After 12 and 36 months of cART 3 % and 8 % of individuals died at HCB, versus 2 % and 4 % at RFH (p < 0.0001). CONCLUSION: In middle-income countries, cART is usually started at an advanced stage of HIV disease, resulting in higher mortality rates than in high income countries, supporting improved testing campaigns for early detection of HIV infection and early introduction of newer cART regimens

Evidence-based selection of training compounds for use in the mechanism-based integrated prediction of drug-induced liver injury in man

The current test systems employed by pharmaceutical industry are poorly predictive for drug-induced liver injury (DILI). The ‘MIP-DILI’ project addresses this situation by the development of innovative preclinical test systems which are both mechanism-based and of physiological, pharmacological and pathological relevance to DILI in humans. An iterative, tiered approach with respect to test compounds, test systems, bioanalysis and systems analysis is adopted to evaluate existing models and develop new models that can provide validated test systems with respect to the prediction of specific forms of DILI and further elucidation of mechanisms. An essential component of this effort is the choice of compound training set that will be used to inform refinement and/or development of new model systems that allow prediction based on knowledge of mechanisms, in a tiered fashion. In this review, we focus on the selection of MIP-DILI training compounds for mechanism-based evaluation of non-clinical prediction of DILI. The selected compounds address both hepatocellular and cholestatic DILI patterns in man, covering a broad range of pharmacologies and chemistries, and taking into account available data on potential DILI mechanisms (e.g. mitochondrial injury, reactive metabolites, biliary transport inhibition, and immune responses). Known mechanisms by which these compounds are believed to cause liver injury have been described, where many if not all drugs in this review appear to exhibit multiple toxicological mechanisms. Thus, the training compounds selection offered a valuable tool to profile DILI mechanisms and to interrogate existing and novel in vitro systems for the prediction of human DILI

Menopause care in women living with HIV in the UK - A review

Advances in HIV care over the last 30 years have transformed a virtually fatal condition into a chronic, manageable one. Antiretroviral therapy (ART) has dramatically changed the outlook for people living with HIV so that most individuals with well controlled disease have a normal life expectancy. As result of this increase in life expectancy, one-third of women living with HIV are of menopausal age. Adding to the shift in age distribution, rates of new HIV diagnosis are increasing in the over 50-year age group, likely the result of a combination of low condom use and perception of transmission risk and in women, an increased risk of HIV acquisition due to the mucosal disruption that accompanies vaginal atrophy. Many women living with HIV are unprepared for menopause, have a high prevalence of somatic, urogenital and psychological symptomatology and low rates of menopausal hormone therapy (MHT) use. Many women experience enormous frustration shuttling between their general practitioner and HIV care provider trying to have their needs met, as few HIV physicians have training in menopause medicine and primary care physicians are wary of managing women living with HIV, in part, because of fears about potential drug-drug interactions (DDIs) between MHT and ART. Several data gaps exist with regard to the relationship between HIV and the menopause, including whether the risk of HIV transmission is increased in virally-suppressed women with vaginal atrophy, whether or not menopause amplifies the effects of HIV on cardiovascular, psychological and bone health, as well as the safety and efficacy of MHT in women living with HIV. Menopausal women living with HIV deserve high quality individualised menopause care that is tailored to their needs. More research is needed in the field of HIV and menopause, primarily on cardiovascular disease and bone health outcomes as well as symptom control, and strategies to reduce HIV acquisition, encourage testing, and maintain older women in care in order to inform optimal clinical management.</p

Multi-lingual and multi-cultural information literacy; perspectives, models and good practice

Purpose This paper reviews current approaches to, and good practice, in information literacy development in multi-lingual and multi-cultural settings, with particular emphasis on provision for international students. Design/methodology/approach A selective and critical review of published literature is extended by evaluation of examples of multi-lingual information literacy tutorials and MOOCs. Findings Multi-lingual and multi-cultural information literacy are umbrella terms covering a variety of situations and issues. This provision is of increasing importance in an increasingly mobile and multi-cultural world. This article evaluates current approaches and good practice, focusing on issues of culture vis a vis language, the balance between individual and group needs, specific and generic information literacy instruction, and models for information literacy, pedagogy and culture. Recommendations for good practice and for further research are given, Originality/value This is one of very few articles critically reviewing how information literacy development is affected by linguistic and cultural factors

Monoubiquitination of syntaxin 3 leads to retrieval from the basolateral plasma membrane and facilitates cargo recruitment to exosomes

Syntaxin 3 (Stx3), a SNARE protein located and functioning at the apical plasma membrane of epithelial cells, is required for epithelial polarity. A fraction of Stx3 is localized to late endosomes/lysosomes, although how it traffics there and its function in these organelles is unknown. Here we report that Stx3 undergoes monoubiquitination in a conserved polybasic domain. Stx3 present at the basolateral—but not the apical—plasma membrane is rapidly endocytosed, targeted to endosomes, internalized into intraluminal vesicles (ILVs), and excreted in exosomes. A nonubiquitinatable mutant of Stx3 (Stx3-5R) fails to enter this pathway and leads to the inability of the apical exosomal cargo protein GPRC5B to enter the ILV/exosomal pathway. This suggests that ubiquitination of Stx3 leads to removal from the basolateral membrane to achieve apical polarity, that Stx3 plays a role in the recruitment of cargo to exosomes, and that the Stx3-5R mutant acts as a dominant-negative inhibitor. Human cytomegalovirus (HCMV) acquires its membrane in an intracellular compartment and we show that Stx3-5R strongly reduces the number of excreted infectious viral particles. Altogether these results suggest that Stx3 functions in the transport of specific proteins to apical exosomes and that HCMV exploits this pathway for virion excretion

Outcomes of MR-guided Stereotactic Body Radiotherapy (SBRT) or yttrium-90 Transarterial Radioembolization for Hepatocellular Carcinoma Treated at an Urban Liver Transplant Center

Background: There are overlapping indications for both stereotactic body radiotherapy (SBRT) and yttrium-90 (Y90) trans-arterial radioembolization as locoregional treatments for hepatocellular cancer, though most centers preferentially use one modality over the other. MR-guided radiation allows both effective on-table localization and integrated motion management as compared with many traditional linear accelerators, allowing SBRT to be done more easily. Y90 radioembolization has been a well-established modality to deliver highly conformal dose due to the localization of the microspheres to the vascular supply of a tumor. We looked at patient characteristics and treatment outcomes for patients receiving MR-guided SBRT or Y90 at an urban transplant center. Objectives: To compare patient characteristics and treatment outcomes of MR-guided SBRT with Y90 transarterial radioembolization in a liver transplant center. Methods: This retrospective single-institution study analyzed patients with HCC treated with SBRT or Y90 from August 2017 to September 2020. To select a patient population eligible for either treatment modality, any Y90 procedures for lesions \u3e 10 cm or for treatment volumes \u3e 1000 cc were omitted from the cohort. A total of 239 patients were included in the analysis, receiving a total of 98 courses of SBRT and 187 courses of Y90 treatment. Local control (LC), freedom from liver progression (FFLP), and overall survival (OS) rates were measured from treatment completion date to death date or last follow-up. All outcomes were censored at time of loss to follow-up; LC and FFLP were censored at time of liver transplant if applicable. Cox regression models were used for survival, with significant factors on the univariate analysis further analyzed with a multivariate model. Results: Median time to follow-up was 11 months (0-44 mo). The mean size of lesions treated with SBRT were smaller than those treated with Y90 (2.7 cm vs 4.3 cm, P\u3c0.01). The groups of patients differed in liver disease characteristics, with SBRT patients having fewer Child-Pugh A disease (62% vs 80%, P\u3c0.01), more having received locoregional treatments to the liver in the past (81% v 35%, P\u3c0.01), and more disease in previously treated liver (57% vs 25%, P\u3c0.01). Dose of radiation for SBRT was 45-50 Gy administered in 5 fractions; dose of Y90 radiation to tumor was prescribed to a median of 235.2 Gy (range 55.8-512.3 Gy). There was a higher rate of one year LC in the SBRT cohort (77% vs 57%, P\u3c0.01), while median FFLP (9 mo vs 8 mo, P=NS) and median OS were not significantly different (24 mo vs 21 mo, P=NS). Multivariate analysis revealed size of largest lesion (P\u3c0.01) was correlated with decreased local control; a 1 cm increase in tumor size was associated with a 25% increased risk of local failure. Subsequent transplant (P\u3c0.01) was the remaining significant factor. Treatment modality did not remain an independent predictor of LC. Predictors of OS in multivariate analysis included age (P=0.01), prior liver treatments (HR 2.86, P\u3c0.01), size of largest lesion (P\u3c0.01), Child-Pugh stage (P\u3c0.01), portal vein thrombosis (HR 1.6, P=0.04), and subsequent liver transplant (HR 0.08, P\u3c0.01). Conclusions: These findings support the effectiveness of both MR-guided SBRT and Y90 transarterial radioembolization in locoregional management of HCC at a single institution despite clear differences in the patient cohorts. Though survival outcomes were comparable, local control differences favored the cohort treated by SBRT, in large part due to differences in tumor size. This data supports further investigation in a randomized study between SBRT and Y90

Computerised interpretation of fetal heart rate during labour (INFANT) : a randomised controlled trial

Background: Continuous electronic fetal heart-rate monitoring is widely used during labour, and computerised interpretation could increase its usefulness. We aimed to establish whether the addition of decision-support software to assist in the interpretation of cardiotocographs affected the number of poor neonatal outcomes. Methods: In this unmasked randomised controlled trial, we recruited women in labour aged 16 years or older having continuous electronic fetal monitoring, with a singleton or twin pregnancy, and at 35 weeks' gestation or more at 24 maternity units in the UK and Ireland. They were randomly assigned (1:1) to decision support with the INFANT system or no decision support via a computer-generated stratified block randomisation schedule. The primary outcomes were poor neonatal outcome (intrapartum stillbirth or early neonatal death excluding lethal congenital anomalies, or neonatal encephalopathy, admission to the neonatal unit within 24 h for >= 48 h with evidence of feeding difficulties, respiratory illness, or encephalopathy with evidence of compromise at birth), and developmental assessment at age 2 years in a subset of surviving children. Analyses were done by intention to treat. This trial is completed and is registered with the ISRCTN Registry, number 98680152. Findings: Between Jan 6, 2010, and Aug 31, 2013, 47 062 women were randomly assigned (23 515 in the decision-support group and 23 547 in the no-decision-support group) and 46 042 were analysed (22 987 in the decision-support group and 23 055 in the no-decision-support group). We noted no difference in the incidence of poor neonatal outcome between the groups-172 (0.7%) babies in the decision-support group compared with 171 (0.7%) babies in the no-decision-support group (adjusted risk ratio 1.01, 95% CI 0.82-1.25). At 2 years, no significant differences were noted in terms of developmental assessment. Interpretation: Use of computerised interpretation of cardiotocographs in women who have continuous electronic fetal monitoring in labour does not improve clinical outcomes for mothers or babies