Foreword

European Union ( EU ) law is no more immune than any other functioning body of law to technological innovation, and the European institutions need to adapt to such change. EU law has done so in a wide variety of ways, only a sampling of which can be presented in this issue of the Columbia Journal of European Law that we are honored to introduce. The Journal\u27s commission of this Special Issue evidences its keen awareness of both the promises and challenges that technological change presents to Europe and its legal institutions

Pattern of congenital abnormalities in a tertiary hospital and its impact on neonatal mortality

Background: Congenital abnormalities are major contributors of neonatal mortality and stillbirths. However, there is not sufficient data in our country on the prevalence of various congenital malformations and their impact on neonatal mortality. Objectives: To study the prevalence and pattern of congenital anomalies among neonates delivered in a tertiary hospital setting in 3 years and its impact on perinatal and neonatal mortality. Materials and Methods: This hospital based prospective descriptive study was undertaken at tertiary care hospital in Kerala. All babies born in the hospital from January 2013 to December 2015 (3 years) were included in the study. The baby was examined by a pediatrician during the first 24 h to identify any birth defects. A detailed history including familial and gestational factors was taken in babies with birth defects. Photographs, radiographs, ultrasound examination, echocardiography, and chromosomal studies were undertaken as required. The details were entered in a pro forma. The anomalies are classified as per ICD-10 criteria. Results were analyzed by simple statistical techniques recording number and percentage of cases. Results: The prevalence of birth defects in live born newborn was 1.9% whereas, in stillbirths, it was 15.3%. Congenital anomalies also contributed a major risk factor for neonatal death as 22% of the newborns, died in the immediate neonatal period, had some form of congenital anomaly. The major maternal risk factor found to be associated with congenital anomalies was gestational diabetes (21.3%). The patterns of congenital anomalies were musculoskeletal anomalies (25%), central nervous system (18%), genitourinary system (14%), congenital diaphragmatic hernia (12%), cardiovascular system (10%), gastrointestinal (7%), syndromes (6%), non-immune hydrops (5%), and others (3%). Conclusion: Prevalence of birth defects in this birth cohort was 1.9% comparable to other Indian data. In Kerala, one of the major causes of perinatal and neonatal mortality is congenital malformations

1,2,3,4-Tetrahydroisoquinolines as inhibitors of HIV-1 integrase and human LEDGF/p75 interaction

Alkaloids are a class of organic compounds with a wide range of biological properties, including anti-HIV activity. The 1,2,3,4-tetrahydroisoquinoline is a ubiquitous structural motif of many alkaloids. Using a short and an efficient route for synthesis, a series of 1,2,3,4-tetrahydroisoquinolines/isoquinolines was developed. These compounds have been analysed for their ability to inhibit an important interaction between HIV-1 integrase enzyme (IN) and human LEDGF/p75 protein (p75) which assists in the viral integration into the active genes. A lead compound 6d is found to inhibit the LEDGF/p75-IN interaction in vitro with an IC50 of similar to 10 mu m. Molecular docking analysis of the isoquinoline 6d reveals its interactions with the LEDGF/p75-binding residues of IN. Based on an order of addition experiment, the binding of 6d or LEDGF/p75 to IN is shown to be mutually exclusive. Also, the activity of 6d in vitro is found to be unaffected by the presence of a non-specific DNA. As reported earlier for the inhibitors of LEDGF/p75-IN interaction, 6d exhibits a potent inhibition of both the early and late stages of HIV-1 replication. Compound 6d differing from the known inhibitors in the chemical moieties and interactions with CCD could potentially be explored further for developing small molecule inhibitors of LEDGF/p75-IN interaction having a higher potency

Weather-wise? Sporting embodiment, weather work and weather learning in running and triathlon

Weather experiences are currently surprisingly under-explored and under-theorised in sociology and sport sociology, despite the importance of weather in both routine, everyday life and in recreational sporting and physical–cultural contexts. To address this lacuna, we examine here the lived experience of weather, including ‘weather work’ and ‘weather learning’, in our specific physical–cultural worlds of distance-running, triathlon and jogging in the United Kingdom. Drawing on a theoretical framework of phenomenological sociology, and the findings from five separate auto/ethnographic projects, we explore the ‘weather-worlds’ and weather work involved in our physical–cultural engagement. In so doing, we address ongoing sport sociological concerns about embodiment and somatic, sensory learning and ways of knowing. We highlight how weather work provides a key example of the phenomenological conceptualisation of the mind–body–world nexus in action, with key findings delineating weather learning across the meteorological seasons that contour our British weather-related training

Values of sexual behaviour in Central and Eastern Europe

Despite the profusion of social cognitive models for the prediction of sexual behaviour, we have only limited knowledge as to the role of individual values in predicting risky sexual activity. This study assessed the relationship between a recently developed value structure and sexual behaviour in the context of rising HIV infection in central and eastern Europe. Five hundred and three respondents (business people, doctors and nurses) from Estonia, Georgia, Hungary, Poland and Russia completed Schwartz’s Portrait Values Questionnaire and reported their condom use, partnership history and record of sexual disease. Results indicated that values had a moderate but consistent relationship with sexual behaviour, with riskier sexual activity reported by those high on Openness to Change, Hedonism and Self-Enhancement. These findings are discussed in the context of the need for culturally sensitive interventions in order to tackle the growing HIV epidemic in this region.This project was supported by a research grant from the Research Support Scheme operated by the Soros Foundation, Prague

Alpha band frontal connectivity is a state-specific electroencephalographic correlate of unresponsiveness during exposure to dexmedetomidine and propofol

Background: Coherent alpha electroencephalogram (EEG) rhythms in the frontal cortex have been correlated with the hypnotic effects of propofol and dexmedetomidine, but less is known about frontal connectivity as a state-specific correlate of unresponsiveness as compared with long-range connectivity. We aimed to distinguish dose- and state-dependent effects of dexmedetomidine and propofol on EEG connectivity.Methods: Forty-seven healthy males received either dexmedetomidine (n=23) or propofol (n =24) as target-controlled infusion with stepwise increments until loss of responsiveness (LOR). We attempted to arouse participants during constant dosing (return of responsiveness [ROR]), and the target concentration was then increased 50% to achieve presumed loss of consciousness. We collected 64-channel EEG data and prefrontal-frontal and anterior-posterior functional connectivity in the alpha band (8-14 Hz) was measured using coherence and weighted phase lag index (wPLI). Directed connectivity was measured with directed phase lag index (dPLI).Results: Prefrontal-frontal EEG-based connectivity discriminated the states at the different drug concentrations. At ROR, prefrontal-frontal connectivity reversed to the level observed before LOR, indicating that connectivity changes were related to unresponsiveness rather than drug concentration. Unresponsiveness was associated with emergence of frontal-to-prefrontal dominance (dPLI: -0.13 to -0.40) in contrast to baseline (dPLI: 0.01-0.02). Coherence, wPLI, and dPLI had similar capability to discriminate the states that differed in terms of responsiveness and drug concentration. In contrast, anterior-posterior connectivity in the alpha band did not differentiate LOR and ROR.Conclusions: Local prefrontal-frontal EEG-based connectivity reflects unresponsiveness induced by propofol or dexmedetomidine, suggesting its utility in monitoring the anaesthetised state with these agents.Clinical trial registration:NCT01889004</div

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

A modular approach toward producing nanotherapeutics targeting the innate immune system.

Immunotherapies controlling the adaptive immune system are firmly established, but regulating the innate immune system remains much less explored. The intrinsic interactions between nanoparticles and phagocytic myeloid cells make these materials especially suited for engaging the innate immune system. However, developing nanotherapeutics is an elaborate process. Here, we demonstrate a modular approach that facilitates efficiently incorporating a broad variety of drugs in a nanobiologic platform. Using a microfluidic formulation strategy, we produced apolipoprotein A1-based nanobiologics with favorable innate immune system-engaging properties as evaluated by in vivo screening. Subsequently, rapamycin and three small-molecule inhibitors were derivatized with lipophilic promoieties, ensuring their seamless incorporation and efficient retention in nanobiologics. A short regimen of intravenously administered rapamycin-loaded nanobiologics (mTORi-NBs) significantly prolonged allograft survival in a heart transplantation mouse model. Last, we studied mTORi-NB biodistribution in nonhuman primates by PET/MR imaging and evaluated its safety, paving the way for clinical translation.This work was supported by NIH grants R01 CA220234, R01 HL144072, P01 HL131478, and NWO/ZonMW Vici 91818622 (to W.J.M.M.); R01 HL143814 and P01HL131478 (to Z.A.F.); R01 AI139623 (to J.O.); and P30 CA008748 (to T.R.). M.M.T.v.L. was supported by the American Heart Association (grant 19PRE34380423). M.G.N. was supported by a Spinoza grant from the Netherlands Organization for Scientific Research and an ERC Advanced Grant (no. 833247); L.A.B.J. was supported by a Competitiveness Operational Programme grant of the Romanian Ministry of European Funds (P_37_762, MySMIS 103587).S

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy