Design of an adaptive randomized clinical trial of intravenous citrulline for sickle cell pain crisis in the emergency department.

Background: Vaso-occlusive pain crisis (VOC) is the most frequent cause for Emergency Department (ED) visits and hospital admissions for patients with sickle cell disease (SCD). Nitric oxide plays a critical role in the pathogenesis of vaso-occlusion. The amino acid, citrulline, is the main endothelial nitric oxide booster that offers the potential to ameliorate vaso-occlusion and decrease the risk of hospitalization. Objective: In this two-part study, the goal of the first part is to determine the pharmacokinetic profile of intravenous (IV) l-citrulline and optimal dose for the second part of the study, which is to determine the efficacy and tolerability of the intervention in patients with SCD. Design: A phase I/IIA open-label dose-finding study with subsequent double-blind, placebo-controlled, randomized Study of l-citrulline in children and adolescents with SCD presenting to the ED in VOC. Methods: Part 1: Subjects experiencing VOC are enrolled in an open-label, ascending dose of IV l-citrulline to identify the optimum dose with endpoints of pharmacokinetic parameters, pain scores, reduction of opioid use, quality of life, proportion admitted to the hospital for treatment of pain, readmission rates, and assessment of adverse events. Part 2 of the trial is a double-blind, placebo-controlled adaptive "pick-the-winner" design to evaluate the efficacy and tolerability of IV l-citrulline in patients with SCD while receiving standard of care therapy for VOC. Summary: This ED based sickle cell adaptive trial will determine the optimal dose for IV citrulline and whether the intervention improves outcome as a potential novel therapy for VOC in SCD.

Neural distinctiveness and reinstatement of hippocampal representations support unitization for associations.

The medial temporal lobe (MTL) is critical to associative memory success, yet not all types of associations may be processed in a similar manner within MTL subregions. In particular, previous work suggests intra- and inter-item associations not only exhibit differences in overall rates of recollection, but also recruit different MTL subregions. Whereas intra-item associations, akin to unitization, take advantage of associations between within-item features, inter-item associations form links across discrete items. The current work examines the neural differences between these two types of associations using fMRI and multivoxel analyses. Specifically, the current study examines differences across face-occupation as a function of whether the pairing was viewed as a person performing the given job (intra-item binding) or a person saying they knew someone who had a particular job (inter-item binding). The results show that at encoding, successfully recollected neural patterns related to intra- and inter-item associations are distinct from one another in the hippocampus, parahippocampal and perirhinal cortex. Additionally, the two trial types are reinstated distinctly such that inter-item trials have higher neural reinstatement from encoding to retrieval compared to intra-item trials in the hippocampus. We conclude that intra- and inter- associative pairs may utilize similar neural regions that represent patterns of activation differentially at encoding. However, to reinstate information to the same degree (i.e., subsequently successfully recollected) inter-item associations, that are all encoded in the same manner, may be reinstated more similarly compared to intra-item associations that are encoded by imagining pairs differently and occupation specific. This may indicate that intra-item associations promote more efficient reinstatement.

First report of human exposure to Hyalomma marginatum in England: Further evidence of a Hyalomma moulting event in north-western Europe?

Hyalomma marginatum is widely distributed across the Mediterranean, Northern Africa and the Middle East. Current climate conditions in Northern Europe are thought to limit the species' ability to moult to the adult stage. It is a vector of several pathogens of human and veterinary concern, including Crimean-Congo haemorrhagic fever virus, for which it is the primary vector in Europe. Here, we report the first human exposure to a locally acquired adult H. marginatum in England, and the second detection in England of Rickettsia aeschlimannii associated with imported Hyalomma.

All-cause and cause-specific mortality following non-traumatic spinal cord injury: evidence from a population-based cohort study in Switzerland.

STUDY DESIGN: Observational cohort study. OBJECTIVE: To benchmark all-cause and cause-specific mortality following NTSCI to the general population (GP). SETTING: Specialized rehabilitation centers in Switzerland. METHODS: Longitudinal data from the Swiss Spinal Cord Injury (SwiSCI) Medical Record study were probabilistically linked with cause of death (CoD) information from the Swiss National Cohort. Standardized mortality ratios (SMRs) were estimated for all-cause and cause-specific mortality. Competing risk frameworks were used to estimate the probability of death due to specific CoD. RESULTS: One thousand five hundred and one individuals were admitted for first rehabilitation with NTSCI between 1990-2011; CoD information was available for 454 individuals of the 525 individuals that died. Overall, the mortality rate for persons with NTSCI was 1.6 times greater than that of the GP. Deaths due to cardiovascular disease (39.8%), neoplasms (22%), and infection (9.9%) were most often reported. Individuals with an SCI due to a vascular etiology indicated the greatest burden of mortality from infection compared with the GP (SMR 5.4; 95% CI, 3.1 to 9.2). CONCLUSIONS: Cause-specific SMRs varied according to etiology. This supports the need for targeted clinical care and follow-up. Cardiovascular disease, neoplasms, and infection, emerged as main causes of death following NTSCI and should thus be targets for future research and differential clinical management approaches.

Experiences of using the toll-free telephone line to access maternal and newborn health services in central Uganda: a qualitative study.

OBJECTIVES: Save the Mothers (STM) operates the toll-free telephone line (TFL) service in nine health facilities in Uganda. The TFL is influential in addressing the first and second delays in seeking care as it connects vulnerable mothers to health facilities at no cost. This study aimed at exploring the experiences of health workers and community members in using the TFL to access maternal and newborn health services in four health facilities in central Uganda. STUDY DESIGN: This phenomenological/qualitative study used focus group discussions (FGDs) to collect data in four health facilities. METHODS: A total of 10 FGDs were conducted; two with health workers, four with women, and another four with both men and women. Each session lasted 45-60 min and had a moderator, observer, and note taker. All discussions were audio-recorded after obtaining consent from the participants. Interviews were transcribed verbatim and translated to English from audio recordings. Data analysis was performed using the thematic analysis using QDA DATA Miner software. RESULTS: The TFL service was pivotal in improving health worker and community relations, relaying timely health advice, ensuring prompt response to obstetric emergencies and facilitated timely referrals. However, the service faced several obstacles: unanswered calls, language differences, poor connectivity/network, and misuse/abuse. CONCLUSION: This study demonstrates the potential of the TFL service in addressing the first and second delay as it allows for timely linkage of vulnerable mothers to health facilities. The TFL enhanced health worker and community relations and facilitated timely referrals and relaying of health advice. Addressing maternal mortality in low-income settings necessitates increased investment and scale up of such high-impact mHealth interventions.

Survival after non-traumatic spinal cord injury: evidence from a population-based rehabilitation cohort in Switzerland.

STUDY DESIGN: Observational cohort study. OBJECTIVE: To investigate survival and life expectancy after NTSCI in Switzerland according to etiology. SETTING: Specialized rehabilitation centers in Switzerland. METHODS: Longitudinal data from the Swiss Spinal Cord Injury (SwiSCI) medical records study were used. Adjusted hazard ratios (HRs) and life expectancies were estimated using flexible parametric survival modeling. RESULTS: One thousand four hundred and fifty individuals were admitted to first rehabilitation for NTSCI between 1990 and 2011, contributing 6137 cumulative person-years at risk and 528 deaths. With reference to persons with a degenerative disc disorder, the HR for mortality in individuals with NTSCIs from infections was 1.42 (95% CI 0.99-2.04), while risk in those with NTSCIs from vascular disorders was 1.28 (95% CI 0.97-1.68). Mortality risk was most pronounced in individuals with NTSCIs from malignant neoplasms (HR 6.32, 95% CI 4.79-8.34). Exemplified for males with an attained age of 60 years, a malignant etiology was associated with 1.7 life years remaining (LYR), as compared to 10.1 LYR for non-malignant etiologies. Males with an attained age of 60 years and a degenerative disc etiology were estimated to have 12.9 LYR. CONCLUSIONS: This study contributes an evidence base for risk factors of mortality after NTSCI, reducing a considerable knowledge gap in survival after NTSCI. Survival and life expectancy estimates were highly differential between etiological groups, indicating a need for a heterogeneous clinical approach and dynamic health-care provisions for this growing population.

Effectiveness of progesterone, cerclage and pessary for preventing preterm birth in singleton pregnancies: a systematic review and network meta-analysis.

BACKGROUND: Preterm birth (PTB) is the leading cause of infant death, but it is unclear which intervention is best to prevent it. OBJECTIVES: To compare progesterone, cerclage and pessary, determine their relative effects and rank them. SEARCH STRATEGY: We searched Medline, EMBASE, CINAHL, Cochrane CENTRAL and Web of Science (to April 2016), without restrictions, and screened references of previous reviews. SELECTION CRITERIA: We included randomised trials of progesterone, cerclage or pessary for preventing PTB in women with singleton pregnancies at risk as defined by each study. DATA COLLECTION AND ANALYSIS: We extracted data by duplicate using a piloted form and performed Bayesian random-effects network meta-analyses and pairwise meta-analyses. We rated evidence quality using GRADE, ranked interventions using SUCRA and calculated numbers needed to treat (NNT). MAIN RESULTS: We included 36 trials (9425 women; 25 low risk of bias trials). Progesterone ranked first or second for most outcomes, reducing PTB < 34 weeks [odds ratio (OR) 0.44; 95% credible interval (CrI) 0.22-0.79; NNT 9; low quality], <37 weeks (OR 0.58; 95% CrI 0.41-0.79; NNT 9; moderate quality), and neonatal death (OR 0.50; 95% CrI 0.28-0.85; NNT 35; high quality), compared with control, in women overall at risk. We found similar results in the subgroup with previous PTB, but only a reduction of PTB < 34 weeks in women with a short cervix. Pessary showed inconsistent benefit and cerclage did not reduce PTB < 37 or <34 weeks. CONCLUSIONS: Progesterone was the best intervention for preventing PTB in singleton pregnancies at risk, reducing PTB < 34 weeks, <37 weeks, neonatal demise and other sequelae. TWEETABLE ABSTRACT: Progesterone was better than cerclage and pessary to prevent preterm birth, neonatal death and more in network meta-analysis.

Seasonality of suicide behavior in Northwest Alaska: 1990-2009.

OBJECTIVES: Suicide is a leading cause of death worldwide, and disproportionately affects Indigenous populations. Seasonal suicide patterns are variable in the literature, and could offer novel approaches to the timing and focus of prevention efforts if better understood. With a suicide surveillance system in place since 1989, this study offers an unprecedented opportunity to explore seasonal variations in both fatal and non-fatal suicide behavior in an Indigenous Arctic region. STUDY DESIGN: Cross-sectional. METHODS: In this descriptive study, we analyzed data collected from 1990 to 2009 in the rural northwest region of Alaska, both graphically and using the chi-squared test for multinomials. RESULTS: We found a significant monthly variation for suicide attempts, with a peak in suicide behavior observed between April and August (P = 0.0002). Monthly variation was more pronounced among individuals ≤29 years of age, and was present in both males and females, although the seasonal pattern differed by sex. CONCLUSIONS: Our findings of a significant seasonal pattern in suicide behavior, with monthly variation (summer peak) in non-fatal suicide behavior among younger age groups, and among both males and females can assist planners in targeting subpopulations for prevention at different times of the year.

Heparin-binding correlates with increased efficiency of AAV1- and AAV6-mediated transduction of striated muscle, but negatively impacts CNS transduction.

Gene delivery vectors derived from adeno-associated virus (AAV) have great potential as therapeutic agents. rAAV1 and rAAV6, efficiently target striated muscle, but the mechanisms that determine their tropism remain unclear. It is known that AAV6, but not AAV1, interacts with heparin-sulfate proteoglycans (HSPG). HSPGs are not primary receptors for AAV6, but heparin interactions may affect tissue tropism and transduction. To investigate these possibilities, we generated rAAV1 and rAAV6 capsids that do or do not bind heparin. We evaluated the transduction profile of these vectors in vivo across multiple routes of administration, and found that heparin-binding capability influences tissue transduction in striated muscle and neuronal tissues. Heparin-binding capsids transduce striated muscle more efficiently than non-binding capsids, via both intramuscular and intravenous injection. However, rAAV6 achieved greater muscle transduction than the heparin-binding rAAV1 variant, suggesting that there are additional factors that influence differences in transduction efficiency between AAV1 and AAV6. Interestingly, the opposite trend was found when vectors were delivered via intracranial injection. Non-binding vectors achieved robust and widespread gene expression, whereas transduction via heparin-binding serotypes was substantially reduced. These data indicate that heparin-binding capability is an important determinant of transduction that should be considered in the design of rAAV-mediated gene therapies.

Sequencing and phylogenetic characterisation of a fatal Crimean - Congo haemorrhagic fever case imported into the United Kingdom, October 2012.

A patient with fever, and haemorrhagic symptoms was admitted to a hospital in Glasgow on 2 October 2012. Since he had returned from Afghanistan, serum samples were sent for diagnosis at the Rare and Imported Pathogens Laboratory, where a real-time reverse transcriptase-PCR diagnosis of Crimean ­ Congo haemorrhagic fever was made within 3 hrs after receipt of the sample. Hereafter the patient was transferred to a high-security infectious diseases unit in London but died on 6 October.

Development of an indirect ELISA method for the parallel measurement of IgG and IgM antibodies against Crimean-Congo haemorrhagic fever (CCHF) virus using recombinant nucleoprotein as antigen.

Recombinant nucleoprotein from Crimean-Congo Haemorrhagic Fever (CCHF) virus was successfully derived from a baculovirus expression system and purified for use in a novel enzyme-linked immunosorbent assay (ELISA) diagnostic test. Comparable tests were used for detection of IgG and IgM antibodies, thus allowing efficient detection of both antibodies in parallel. The major benefits of the assay also included removing any requirement for polyclonal sera, thus eliminating variation in preparations and allowing standardisation between laboratories. The assay was successfully tested using a panel of positive sera supplied from samples identified as being positive in Turkey, Tajikistan and Kosovo and shown to be sensitive and specific. It is envisaged that this simple diagnostic ELISA for CCHF virus infection which removes the reliance on polyclonal antibody preparations, will be accessible to a wider range of laboratories enabling them to carry out routine diagnosis. This will improve the efficiency of diagnosis and subsequent management of infected patients.

Anxiety, psychosis and substance use: prevalence, correlates and recognition in an outpatient mental health setting.

OBJECTIVE: The current study examined anxiety in people with substance use disorder (SUD) and a psychotic disorder. It is hypothesised that: anxiety disorders (AD) would be highly prevalent (greater than 20%) in people identified as having SUD and psychotic disorders; those with comorbid AD would fair worse than those without, on measures of quality of life, severity of substance dependence, locus of control, suicidality and psychotic symptoms; and, the presence of such anxiety disorder symptomatology would be under-detected by their mental health case managers. METHOD: Outpatients with co-occurring substance use disorder and psychosis were interviewed to collect data about their diagnosis, depressive and psychotic symptoms, severity of dependence on substances, quality of life and locus of control. Participants' case managers made blind ratings of the presence and severity of participants' anxiety. RESULTS: Fifty eight percent of participants had at least one anxiety disorder. Of these, 56% - 70% had case managers who had identified them as having an anxiety problem. The occurrence of anxiety disorder was associated with more external locus of control, greater intensity of suicidal thinking, worse psychotic symptoms, lower quality of life and greater severity of dependence on substances. CONCLUSION: This research suggests anxiety in people with substance use disorder and psychosis is highly prevalent, is associated with poorer outcomes, and is under detected by case managers. Further examination of this issue may lead to important advances in the treatment and prognosis of people with substance use disorder and psychosis.

Terahertz near-field imaging using subwavelength plasmonic apertures and a quantum cascade laser source.

The first demonstration, to our knowledge, of near-field imaging using subwavelength plasmonic apertures with a terahertz quantum cascade laser source is presented. "Bull's-eye" apertures, featuring subwavelength circular apertures flanked by periodic annular corrugations were created using a novel fabrication method. A fivefold increase in intensity was observed for plasmonic apertures over plain apertures of the same diameter. Detailed studies of the transmitted beam profiles were undertaken for apertures with both planarized and corrugated exit facets, with the former producing spatially uniform intensity profiles and subwavelength spatial resolution. Finally, a proof-of-concept imaging experiment is presented, where an inhomogeneous pharmaceutical drug coating is investigated.

Negative refraction and the spectral filtering of terahertz radiation by a photonic crystal prism.

We demonstrate how micromachined photonic crystals can be used to negatively refract terahertz frequency light. The photonic crystals, which are constructed from conventional dielectric materials, manipulate the incident beam via interaction with their photonic bands. Consequently, we show that different components of a broadband beam incident on the structure may be positively or negatively refracted, depending upon its frequency and that the structure can be used as an effective spectral filter of THz radiation.

Microarchitecture is severely compromised but motor protein function is preserved in dystrophic mdx skeletal muscle.

Progressive force loss in Duchenne muscular dystrophy is characterized by degeneration/regeneration cycles and fibrosis. Disease progression may involve structural remodeling of muscle tissue. An effect on molecular motorprotein function may also be possible. We used second harmonic generation imaging to reveal vastly altered subcellular sarcomere microarchitecture in intact single dystrophic mdx muscle cells (approximately 1 year old). Myofibril tilting, twisting, and local axis deviations explain at least up to 20% of force drop during unsynchronized contractile activation as judged from cosine angle sums of myofibril orientations within mdx fibers. In contrast, in vitro motility assays showed unaltered sliding velocities of single mdx fiber myosin extracts. Closer quantification of the microarchitecture revealed that dystrophic fibers had significantly more Y-shaped sarcomere irregularities ("verniers") than wild-type fibers (approximately 130/1000 microm(3) vs. approximately 36/1000 microm(3)). In transgenic mini-dystrophin-expressing fibers, ultrastructure was restored (approximately 38/1000 microm(3) counts). We suggest that in aged dystrophic toe muscle, progressive force loss is reflected by a vastly deranged micromorphology that prevents a coordinated and aligned contraction. Second harmonic generation imaging may soon be available in routine clinical diagnostics, and in this work we provide valuable imaging tools to track and quantify ultrastructural worsening in Duchenne muscular dystrophy, and to judge the beneficial effects of possible drug or gene therapies.

Platelet P2Y(12) receptor influences the vessel wall response to arterial injury and thrombosis.

BACKGROUND: Platelets are believed to play an important role in atherogenesis and the vessel response to vascular injury. The P2Y(12) receptor (P2Y(12)) plays a central role in amplifying platelet aggregation, dense granule and alpha-granule secretion, P-selectin expression, microparticle formation, and procoagulant membrane changes, regardless of the activating stimulus. We hypothesized that P2Y(12) deficiency might reduce the vessel wall response to vascular injury as well as thrombosis in murine vascular injury models. METHODS AND RESULTS: P2Y(12)-deficient (-/-) mice and littermate controls (+/+) were bred on a C57 BL/6 background. In vivo murine models of arterial injury were employed alone and in combination with bone marrow transplantation to investigate the role of P2Y(12) in the vessel wall response to arterial injury and thrombosis. At 21 days after ferric chloride injury, neointima formation in P2Y(12)(-/-) arteries was significantly less than that observed in control strain arteries (P<0.025). In agreement with this, the intima-media ratio was significantly greater in femoral wire-injured arteries from P2Y(12)(+/+) compared with P2Y(12)(-/-) animals (P<0.05). Bone marrow transplantation was used to examine the importance of vessel wall P2Y(12) versus platelet P2Y(12). Analysis of arterial sections from chimeric animals at 21 days after injury revealed a smaller intima-media ratio in -/- to +/+ animals than in the positive (+/+ to +/+) control group (P<0.01). CONCLUSIONS: These data demonstrate a role for platelet P2Y(12) in the vessel wall response to arterial injury and thrombosis. This illustrates the manner in which platelets may contribute to atherogenesis and restenosis.

Negative refraction can make non-diffracting beams.

We report the results of simulations relating to the illumination of a structure consisting of a slab constructed from a 2-D hexagonal array of metal rods with a terahertz frequency source. As a consequence of negative refraction an essentially non-divergent beam pattern is observed. Although the results presented relate to the terahertz regime they should also be applicable at other frequencies.

Preliminary evaluation of exotic tick species and exotic pathogens imported on migratory birds into the British Isles.

Field studies were carried out to determine whether ticks are being imported into the British Isles on migratory birds. During spring and autumn migration 2004, ticks were collected from ringed birds at 11 bird observatories and 3 inland Riparia riparia colonies. A total of 38 ticks of 4 species (Ixodes ricinus, I. frontalis, I. lividus, I. arboricola) were collected from 12 species of bird. Ticks were tested for viruses in the Flavivirus and Nairovirus genera, with no positives found. This data demonstrates that ticks are being imported into the British Isles on migratory birds with future work recommended to determine the quantity of ticks imported and to detect low prevalence pathogens.

Terahertz filter based on refractive properties of metallic photonic crystal.

We propose a new type of pass-band filter, in this case designed to operate in the terahertz frequency regime, possessing two separate passbands utilizing the distinction between positive and negative refraction in a photonic crystal prism. The prism is formed from a two-dimensional hexagonal arrangement of metallic rods. In order to understand the operation of the filter we both consider the photonic bandstructure of the associated infinite photonic structure and carry out simulations of the refraction properties of the prism using finite-difference time-domain software.

Unloaded speed of shortening in voltage-clamped intact skeletal muscle fibers from wt, mdx, and transgenic minidystrophin mice using a novel high-speed acquisition system.

Skeletal muscle unloaded shortening has been indirectly determined in the past. Here, we present a novel high-speed optical tracking technique that allows recording of unloaded shortening in single intact, voltage-clamped mammalian skeletal muscle fibers with 2-ms time resolution. L-type Ca(2+) currents were simultaneously recorded. The time course of shortening was biexponential: a fast initial phase, tau(1), and a slower successive phase, tau(2,) with activation energies of 59 kJ/mol and 47 kJ/mol. Maximum unloaded shortening speed, v(u,max), was faster than that derived using other techniques, e.g., approximately 14.0 L(0) s(-1) at 30 degrees C. Our technique also allowed direct determination of shortening acceleration. We applied our technique to single fibers from C57 wild-type, dystrophic mdx, and minidystrophin-expressing mice to test whether unloaded shortening was affected in the pathophysiological mechanism of Duchenne muscular dystrophy. v(u,max) and a(u,max) values were not significantly different in the three strains, whereas tau(1) and tau(2) were increased in mdx fibers. The results were complemented by myosin heavy and light chain (MLC) determinations that showed the same myosin heavy chain IIA profiles in the interossei muscles from the different strains. In mdx muscle, MLC-1f was significantly increased and MLC-2f and MLC-3f somewhat reduced. Fast initial active shortening seems almost unaffected in mdx muscle.