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The incidence of infective endocarditis related to injection drug use is increasing. On the basis of clinical practice and epidemiological and in-vitro data, we postulated that exposure to controlled-release hydromorphone is associated with an increased risk of infective endocarditis among people who inject drugs.We used linked health administrative databases in Ontario, Canada, to assemble a retrospective cohort of adults (aged 18-55 years) who inject drugs for the period of April 1, 2006, to Sept 30, 2015. Cases of infective endocarditis among this cohort were identified using International Classification of Diseases 10 codes. We estimated exposure to hydromorphone and risk of infective endocarditis among this cohort in two ways. First, in a population-level analysis, we identified patients living in regions with high (≥25%) and low (≤15%) hydromorphone prescription rates and, after matching 1:1 on various baseline characteristics, compared their frequency of infective endocarditis. Second, in a patient-level analysis including only those with prescription drug data, we identified those who had filled prescriptions (ie, received the drug from the pharmacy) for controlled-release or immediate-release hydromorphone and, after matching 1:1 on various baseline characteristics, compared their frequency of infective endocarditis with that of patients who had filled prescriptions for other opioids.Between April 1, 2006, and Sept 30, 2015, 60 529 patients had evidence of injection drug use, 733 (1·2%, 95% CI 1·1-1·3) of whom had infective endocarditis. In the population-level analysis of 32 576 matched patients, we identified 254 (1·6%) admissions with infective endocarditis in regions with high hydromorphone use and 113 (0·7%) admissions in regions with low use (adjusted odds ratio [OR] 2·2, 95% CI 1·8-2·8, p0·0001). In the patient-level analysis of 3884 matched patients, the frequency of infective endocarditis was higher among patients who filled prescriptions for hydromorphone than among those who filled prescriptions for non-hydromorphone opioids (2·8% [109 patients] vs 1·1% [41 patients]; adjusted OR 2·5, 95% CI 1·8-3·7, p0·0001). This significant association was seen for controlled-release hydromorphone (3·9% [73 of 1895 patients] vs 1·1% [20 of 1895]; adjusted OR 3·3, 95% CI 2·1-5·6, p0·0001), but not for immediate-release hydromorphone (1·8% [36 of 1989] vs 1·1% [21 of 1989]; 1·7, 0·9-3·6, p=0·072.Among people who inject drugs, the risk of infective endocarditis is significantly higher for those exposed to controlled-release hydromorphone than to other opioids. This association might be mediated by the controlled-release mechanism and should be the subject of further investigation.Ontario Ministry of Health and Long-Term Care, Academic Medical Organization of Southwestern Ontario, Schulich School of Medicine and Dentistry (Western University), and Lawson Health Research Institute.

Three hospital emergency rooms (ERs) routinely referred all cases of cellulitis requiring outpatient intravenous antibiotics, to a central ER-staffed cellulitis clinic. We performed a retrospective cohort study of all patients seen by the ER clinic in the last 4months preceding a policy change (ER management cohort [ERMC]) (n=149) and all those seen in the first 3months of a new policy of automatic referral to an infectious disease (ID) specialist-supervised cellulitis clinic (ID management cohort [IDMC]) (n=136). Fifty-four (40%) of 136 patients in the IDMC were given an alternative diagnosis (noncellulitis), compared to 16 (11%) of 149 in the ERMC (P0.0001). Logistic regression-demonstrated rates of disease recurrence were lower in the IDMC than the ERMC (hazard ratio [HR], 0.06; P=0.003), as were rates of hospitalization (HR, 0.11; P=0.01). There was no significant difference in mortality. Automatic ID consultation for cellulitis was beneficial in differentiating mimickers from true cellulitis, reducing recurrence, and preventing hospital admissions.

Background: For patients hospitalized with severe influenza A, morbidity and mortality remain high. MHAA4549A, a human monoclonal antibody targeting the influenza A hemagglutinin stalk, has demonstrated pharmacological activity in animal studies and in a human influenza A challenge study. We evaluated the safety and efficacy of MHAA4549A plus oseltamivir (OS) against influenza A infection in hospitalized patients. Methods: The CRANE trial was a phase 2b, randomized, double-blind, placebocontrolled study of single intravenous (IV) doses of placebo, 3600-mg, or 8400-mg MHAA4549A, all in combination with oral oseltamivir (+OS) in patients hospitalized with severe influenza A. Patients were enrolled across 68 clinical sites in 18 countries and randomized 1:1:1 into the three cohorts. The primary endpoint was the median time to normalization of respiratory function defined as the time to removal of supplemental oxygen support to maintain a stable SpO2 ≥ 95%. Findings: 166 patients were randomized and analyzed during a preplanned interim analysis (placebo+OS: 56; 3600-mg MHAA4549A+OS: 55; 8400-mg MHAA4549A+OS: 47). Compared to placebo+OS, MHAA4549A+OS did not significantly affect the time to normalization of respiratory function (placebo+OS: 4·28 days (80% CI: 3·06, 6·60); 3600-mg MHAA4549A+OS: 2·78 days (80% CI: 2·52, 4·20); 8400-mg MHAA4549A+OS: 2·65 days (80% CI: 1·58, 4·52). Patient deaths comprised 4 of 9, 6 of 13, and 4 of 9 study discontinuations in each of those treatment arms, respectively. Frequency of adverse events between treatment arms was not significantly different (placebo+OS: 45 (80·4%); 3600-mg MHAA4549A+OS: 37 (67·3%); 8400-mg MHAA4549A+OS: 35 (74·5%)). Interpretation: In hospitalized patients with influenza A, MHAA4549A did not improve clinical outcomes over oseltamivir alone. Variability in patient removal from oxygen supplementation limited the utility of the primary endpoint. Validated endpoints are needed to assess novel treatments for severe influenza A. Trial Registration: This completed trial was registered under ClinicalTrials.gov #NCT02293863 and EudraCT #2014- 000461-43. Funding Statement: Genentech, Inc. provided funding for this study. Declaration of Interests: JJL, PK, JMM, RD, CL, XY, AN, PH, MM, AC, MCP, JG, TC, EMN, and JAT were employees of Genentech, Inc., a member of the Roche group, and own/owned Roche stock and/or options at the time this study was performed. Genentech, Inc. provided research funding to the institutions of ACN, MS, and NA for the conduct of this study. AC is currently an employee of Calico Life Sciences, LLC. Ethics Approval Statement: The CRANE trial was conducted in full conformance with the International Council for Harmonisation (ICH) E6 guideline for Good Clinical Practice (GCP) and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research is conducted, whichever afforded the greater protection to the individual. The study complied with the requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). Studies conducted in the European Union (EU) or European Economic Area complied with the EU Clinical Trial Directive (2001/20/EC). All patients or their legally authorized representative provided written, informed consent.

In a series of three experiments, we explored the nature of implicit representations in change blindness (CB). Using 3 x 3 letter arrays, we asked subjects (Ss) to locate changes in paired arrays separated by 80 ms ISIs, in which one, two or three letters of a row in the second array changed. In one testing version, a tone followed the second array, signaling a row for partial report (PR). In the other version, no PR was required. After Ss reported whether a change had been detected and the PR had been completed (if required), they were asked to identify a degraded letter trigram that was either novel, or from a previously shown row (repetition priming). Our findings indicate that when CB occurs, both the pre-change and post-change stimulus information primes despite its unavailability to consciousness. Surprisingly, findings also indicate that when change detection occurs only the post-change information primes.

Background Concerns about the safety of pediatric oral sedation and the incremental use of triazolam in adults prompted a workshop cosponsored by several professional organizations. Overview There is a strong need and demand for adult and pediatric sedation services. Using oral medication to achieve anxiolysis in adults appears to have a wide margin of safety. Mortality and serious morbidity, however, have been reported with oral conscious sedation, especially in young children. Most serious adverse events are related to potentially avoidable respiratory complications. Conclusions Clinical trials are needed to evaluate oral sedative drugs and combinations, as well as to develop discharge criteria with objective quantifiable measures of home readiness. Courses devoted to airway management should be developed for dentists who provide conscious sedation services. State regulation of enteral administration of sedatives to achieve conscious sedation is needed to ensure safety. Practice Implications Safety in outpatient sedation is of paramount concern, with enteral administration of benzodiazepines appearing safe but poorly documented in the office setting. Conscious sedation by the enteral route, including incremental triazolam, necessitates careful patient evaluation, monitoring, documentation, facilities, equipment and personnel as described in American Dental Association and American Academy of Pediatric Dentistry guidelines.

Background Budesonide is the only inhaled corticosteroid to be given a category B pregnancy rating by the US Food and Drug Administration, based on observational data from the Swedish Medical Birth Registry. However, data from large randomized controlled trials are lacking. Objective To compare pregnancy outcomes among patients with recent-onset mild-to-moderate persistent asthma receiving low-dose budesonide vs placebo. Methods In a randomized, double-blind, placebo-controlled trial, 7,241 patients aged 5 to 66 years with mild-to-moderate persistent asthma for less than 2 years and no previous regular corticosteroid therapy received once-daily budesonide or placebo via dry powder inhaler in addition to their usual asthma medication for 3 years. This trial was followed by a 2-year open-label treatment period. The daily dose of budesonide was 400 μg for adults. The study included 2,473 females aged 15 to 50 years at randomization. Pregnancy was not an exclusion criterion (except for US patients). Results Of 319 pregnancies reported, 313 were analyzed. Healthy children were delivered in 81% and 77% of all pregnancies in the budesonide and placebo groups, respectively. Of the 196 pregnancies reported by participants taking budesonide, 38 (19%) had adverse outcomes: 23 (12%) had miscarriages, 3 (2%) had congenital malformations, and 12 (6%) had other outcomes. Of the 117 pregnancies reported in the placebo group, 27 (23%) had adverse outcomes: 11 (9%) had miscarriages, 4 (3%) had congenital malformations, and 12 (10%) had other outcomes. Conclusions Treatment with low-dose inhaled budesonide in females with mild-to-moderate persistent asthma does not seem to affect the outcome of pregnancy.

Background : Studies into the effects of salbutamol in the treatment of wheeze in infancy have been conflicting, possibly due to differences in outcome variables. We aimed to assess the response to salbutamol using indices derived from passive and forced expiration. Methods : We recruited 39 infants who had a history of wheezing (mean age 43 weeks) and measured maximum flow at functional residual capacity (V′maxFRC) by rapid thoracoabdominal compression (RTC), and forced expired volume at 0.4s (FEV 0.4 ) using the raised-volume RTC technique (RV-RTC). We calculated passive compliance ( C rs ), resistance ( R rs ) and time constant ( τ ) from relaxed expirations that followed the augmented inspirations delivered during RV-RTC. Measurements were repeated after aerosol salbutamol (800mcg). Results : Data were obtained in 32 infants for V′maxFRC, 22 for FEV 0.4 and 19 for passive mechanics. There were no mean changes in any index of forced expiration after salbutamol. Some individuals showed significant changes (improvement or worsening) in one or other index. Overall, there was a small increase in C rs after salbutamol but no change in R rs or τ . Conclusions : We found no consistent pattern of response in either index of forced expiration. Validated clinical scores or alternative physiological techniques may be preferable to respiratory mechanics in assessing bronchodilator response.

Background This study examines the following questions: In moderately disabled readers, will temporal vision-processing therapy procedures that benefit reading comprehension, visual attention, and oculomotor skills ameliorate M-cell processing deficits as measured with coherent motion threshold testing ? And will the results show a corresponding improvement in oral reading and verbal skills? Method A sample of 16 moderately disabled readers, evaluated in a study completed 6 months earlier, were retested with another form of the Gates–MacGinitie Reading Test. Each participant was additionally tested for coherent motion, oral reading, and word attack skills. During the succeeding 6 months, fifteen 45-minute therapy sessions were administered once a week (as the school schedule permitted). After completing 15 therapy sessions, the initial testing procedures were repeated. Results All four variables—namely, Gates–MacGinitie Reading Test, Coherent Motion Threshold Test, Gray Oral Reading Test, and Woodcock-Johnson Word Attack Test— revealed significant improvements after temporal vision therapy. Half of the 16 participants improved 2 or more years in reading comprehension, compared to no significant mean difference following the 6-month “control period” before the onset of therapy. Conclusions This research supports the value of rendering temporal vision therapy to children identified as moderately reading disabled (RD). The diagnostic procedures and the dynamic therapeutic techniques discussed in this article have not been previously used for the specific purpose of ameliorating an M-cell deficit. Improved temporal visual-processing skills and enhanced visual motion discrimination appear to have a salutary effect on magnocellular processing and reading comprehension in RD children with M-cell deficits.

We measured arterial diameter as a function of generation number (#) in the arteriograms of six postmortem lung preparations from human infants aged 35 to 48 wks post-conceptional age (PCA). The log-log plot of mean diameter as a function of generation number revealed a linear decrease in mean and median diameter with increasing #, which was characterized by its slope alpha and intercept beta (linear regression). The mean arterial diameter per generation as well as the ratio (F) between mother and larger daughter branch and the relative ratio of asymmetry (A) between the larger and the smaller daughter branch was calculated. The values of F(#) and A(#) were found to be constant between 2 and 15 generations in individual lungs which is consistent with the pulmonary arterial tree exhibiting fractal properties. The averaged values (F and A within a subject) of F(#) and A(#) as well as alpha and beta were determined for each lung preparation and found to be constant from 35 to 48 weeks of age, revealing unchanged branching properties in the pre- and postnatal phase of human lung development.

This article evaluates a motivational intervention based on the theory of planned behavior, a volitional intervention based on implementation intentions, and a combined motivational plus volitional intervention in promoting attendance at workplace health and safety training courses in the UK. Intervention manipulations were embedded in postal questionnaires completed by participants (N=271). Subsequent attendance over a 3-month period was determined from course records. Findings showed that the volitional and combined interventions doubled the rate of attendance compared to the motivational and control conditions (rates were 39%, 32%, 12%, and 16%, respectively). The effects of the volitional intervention were independent of the effects of previous attendance, demographic variables, employment characteristics, and variables from the theory of planned behavior.

Attention is necessary for the conscious perception of any object. Objects not attended to are not seen. What is it that captures attention when we are engaged in some attention-absorbing task? Earlier research has shown that there are only a very few stimuli which have this power and therefore are reliably detected under these conditions (for example, Mack & Rock, 1998; Moray, 1959). The two most reliable are the observer's own name and a happy face icon which seem to capture attention by virtue of their meaning. Three experiments are described which explore whether these stimuli are detected under conditions, heretofore unexamined, which either cause inattentional blindness or are associated with a perceptual failure associated with the limits of attention. The evidence obtained indicates that these stimuli have a unique capacity to capture and extend the limits of attention under conditions in which this has been deemed highly unlikely.

This is the authors final draft of the version published as The Lancet, 2007, 370(9589), pp.717-719. The published paper can be accessed www.sciencedirect.com.

W. Cherniak, B. Dreifuss, J. Evert, M. Dacso, H.C. Lin, L. Loh; Bridge to Health Medical and Dental, Toronto, ON/CA, University of Arizona College of Medicine Tucson; Global Emergency Care Collaborative, Tucson, AZ/US, University of California San Francisco, San Francisco, CA/US, University of Texas Medical Branch, Galveston, TX/US, University of Pennsylvania School of Medicine, Philadelphia, PA/US, The 53rd Week Ltd., Vancouver, BC/CA

Two patients with oliguric acute renal failure (ARF) attributed to crystalluria and nephrolithiasis with obstructive uropathy caused by the human immunodeficiency virus protease inhibitor indinavir are described. In both patients, ARF resolved with administration of intravenous fluids. One patient required urologic intervention to relieve bilateral ureteral obstruction.

8 newborn babies with airways inflammation, who were mechanically ventilated, underwent bronchoalveolar lavage to examine the fate of neutrophils in the inflamed airways. Light microscopy and electronmicroscopy showed evidence of neutrophil apoptosis and ingestion of intact neutrophils by macrophages in specimens from all 8 infants. Neutrophil apoptosis, without the local release of intracellular contents that promote inflammation, might represent a mechanism by which tissue injury is reduced during the resolution of neonatal pulmonary inflammation.

The kinetics of D-glucose transport over the concentration range 0.07--20 mM have been investigated in a vesiculated membrane preparation from dog kidney cortex. 1. A sodium-dependent and a sodium-independent component of D-glucose uptake are observed. The sodium-dependent component is phlorizin sensitive (KI approximately 0.6 micron) and electrogenic. 2. The sodium-dependent component of D-glucose uptake yields non-linear Eadie-Hofstee plots consistent with the presence of high (GH) and low (GL) affinity sites (KH approximately 0.2 mM, KL approximately 4.5 mM, VL/VH approximately 7 at pH 7.4, 25 degrees C, 100 mM NaC1 gradient). Alternative explanations are cooperative effects of non-Michaelis-Menten kinetics. 3. The initial uptake of D-glucose increases as the intravesicular membrane potential become more negative but the numerical values of KH and KL show little, if any, change. 4. alpha-Methyl-D-glucoside transport is also sodium dependent and phlorizin sensitive (KI approximately 1.9 micron). 5. In contrast to the results for D-glucose, the sodium-dependent component of alpha-methyl-D-glucoside uptake exhibits a nearly linear Eadie-Hofstee plot consistent with a single carrier site with Km approximately 1.9 mM and Vmax approximately 27 nmol/min per mg protein at pH 7.4, 25 degrees C, 100 mM NaCl gradient. 6. The kinetics of D-glucose transport in newborn dog kidney are similar to those in the adult except that the low affinity (GL) system appears to be less well developed.

Site-specific inversion of a controlling element is responsible for flagellar phase transition in Salmonella. When a 900 bp DNA sequence is in one configuration, it allows the expression of the H2 gene, a structural gene which codes for the flagellar antigen. When it is in the opposite configuration, the H2 gene is not expressed. A hybrid λ phage containing the invertible control region and the adjacent H2 gene was constructed, and expression of the H2 gene was shown to be regulated by the orientation of the inversion region. Transposon Tn5 insertion derivatives of this hybrid phage were isolated and λ H2::Tn5 mutants defective for inversion ( H2 switching) were selected and characterized. Two classes of switching phenotypes were observed among the mutants—those which had slightly reduced frequencies of transition from expression of the H2 gene ( H2 on) to nonexpression ( H2 off) (intermediate class) and those in which the frequency of transition was reduced at least three orders of magnitude (null class). Physical mapping of the Tn5 insertion sites revealed that in all mutants the insertion was located inside the inversion region. Tn5 insertion sites in the null class of mutants defined a region of DNA including approximately 500 bp which was necessary for inversion. Genetic complementation tests showed that these λ H2::Tn5 mutants could invert the H2 gene control element if the 500 bp region was introduced in the trans configuration. It is concluded that a gene is located inside the inversion segment and codes for a protein which is required for the inversion event. Furthermore, the two sites at which the crossover event occurred functioned in a cis configuration and were required for inversion. The presence of a gene which is involved in controlling site-specific recombination events may be a general feature of transposon-like elements.

The pulse-injection indicator-dilution technique in vivo has been used to study the interaction of 5-thio-D-glucose and methyl-beta-D-thiogalactopyranoside with renal tubular surfaces in dog kidney. (i) 5-Thio-D-glucose and methyl-beta-D-thiogalactopyranoside have nor antiluminal interaction. (ii) 37 +/- 5% of 5-thio-D-glucose is extracted at the luminal surface relative to simultaneously filtered creatinine. (iii) Luminal extraction of 5-thio-D-glucose is blocked by preloading with D-glucose and phlorizin. (iv) Methyl-beta-D-thiogalactopyranoside in contrast to D-galactose has not luminal interaction. It is concluded that 5-thio-D-glucose shares the glucose transporter at the luminal surface of the proximal tubule. The data also suggest that the ring oxygen participates in the interaction of pyranosides with luminal and antiluminal membrane carriers. At the luminal surface, its absence is quantitatively important while at the antiluminal surface it is apparently essential for the sugar-transporter interaction.