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Circadian rhythms are generated by interlocked transcriptional-translational feedback loops of circadian clock genes and their protein products. Mice homozygous for a functional deletion in the Period-2 gene ( Per2m/m mice) exhibit short free-running circadian periods and eventually lose behavioral circadian rhythmicity in constant darkness (DD). We investigated Per2m/m mice in DD for several months and identified a categorical sex difference in the dependence on Per2 for maintenance of circadian rhythms. Nearly all female Per2m/m mice became circadian arrhythmic in DD, whereas free-running rhythms persisted in 37% of males. Remarkably, with extended testing, Per2m/m mice did not remain arrhythmic in DD, but after varying intervals spontaneously recovered robust, free-running circadian rhythms, with periods shorter than those expressed prior to arrhythmia. Spontaneous recovery was strikingly sex-biased, occurring in 95% of females and 33% of males. Castration in adulthood resulted in male Per2m/m mice exhibiting female-like levels of arrhythmia in DD, but did not affect spontaneous recovery. The circadian pacemaker of many gonad-intact males, but not females, can persist in DD for long intervals without a functional PER2 protein; their circadian clocks may be in an unstable equilibrium, incapable of sustaining persistent coherent circadian organization, resulting in transient cycles of circadian organization and arrhythmia.

The Ozone Mapping and Profiler Suite (OMPS) Nadir Profilers (NPs) are advanced backscatter ultraviolet (BUV) hyperspectral instruments that measure ozone profiles in the Earth atmosphere. The first NP sensor onboard the Suomi National Polar-orbiting Partnership (Suomi-NPP) satellite began its science observations on January 26, 2012, after its aperture door opened. The second OMPS NP, flying on the NOAA-20 satellite, opened its aperture door on January 8, 2018, starting science its data collection. The two NP sensors acquire Earth spectral images along their satellite flight path with a 16.7° wide swath, enabling weekly coverage of vertical ozone distribution in the Earth atmosphere. A successful thorough sensor calibration enables the NP sensors’ data records (SDRs) to meet measurement accuracy requirements. The largest error term in the albedo calibration came from the spectral wavelength calibration. This article provides SDRs accuracy analysis for both NP sensors and discusses important aspects of the SDRs performance in relation to the sensors’ characterization and calibration.

Dynamic fibroblast to myofibroblast state transitions underlie the heart's fibrotic response. Because transcriptome maturation by muscleblind-like 1 (MBNL1) promotes differentiated cell states, this study investigated whether tactical control of MBNL1 activity could alter myofibroblast activity and fibrotic outcomes. In healthy mice, cardiac fibroblast-specific overexpression of MBNL1 transitioned the fibroblast transcriptome to that of a myofibroblast and after injury promoted myocyte remodeling and scar maturation. Both fibroblast- and myofibroblast-specific loss of MBNL1 limited scar production and stabilization, which was ascribed to negligible myofibroblast activity. The combination of MBNL1 deletion and injury caused quiescent fibroblasts to expand and adopt features of cardiac mesenchymal stem cells, whereas transgenic MBNL1 expression blocked fibroblast proliferation and drove the population into a mature myofibroblast state. These data suggest MBNL1 is a post-transcriptional switch, controlling fibroblast state plasticity during cardiac wound healing.

The long-term record of Umkehr measurements from four NOAA Dobson spectrophotometers was reprocessed after updates to the instrument calibration procedures. In addition, a new data quality-control tool was developed for the Dobson automation software (WinDobson). This paper presents a comparison of Dobson Umkehr ozone profiles from NOAA ozone network stations – Boulder, the Haute-Provence Observatory (OHP), the Mauna Loa Observatory (MLO), Lauder – against several satellite records, including Aura Microwave Limb Sounder (MLS; ver. 4.2), and combined solar backscatter ultraviolet (SBUV) and Ozone Mapping and Profiler Suite (OMPS) records (NASA aggregated and NOAA cohesive datasets). A subset of satellite data is selected to match Dobson Umkehr observations at each station spatially (distance less than 200 km) and temporally (within 24 h). Umkehr Averaging kernels (AKs) are applied to vertically smooth all overpass satellite profiles prior to comparisons. The station Umkehr record consists of several instrumental records, which have different optical characterizations, and thus instrument-specific stray light contributes to the data processing errors and creates step changes in the record. This work evaluates the overall quality of Umkehr long-term measurements at NOAA ground-based stations and assesses the impact of the instrumental changes on the stability of the Umkehr ozone profile record. This paper describes a method designed to correct biases and discontinuities in the retrieved Umkehr profile that originate from the Dobson calibration process, repair, or optical realignment of the instrument. The Modern-Era Retrospective analysis for Research and Applications version 2 (MERRA-2) Global Modeling Initiative (M2GMI) and NASA Global Modeling Initiative chemistry transport model (GMI CTM) ozone profile model output matched to station location and date of observation is used to evaluate instrumental step changes in the Umkehr record. Homogenization of the Umkehr record and discussion of the apparent stray light error in retrieved ozone profiles are the focus of this paper. Homogenization of ground-based records is of great importance for studies of long-term ozone trends and climate change.

During heart transplantation, storage in cold preservation solution is thought to protect the organ by slowing metabolism; by providing osmotic support; and by minimising ischaemia-reperfusion (IR) injury upon transplantation into the recipient1,2. Despite its widespread use our understanding of the metabolic changes prevented by cold storage and how warm ischaemia leads to damage is surprisingly poor. Here, we compare the metabolic changes during warm ischaemia (WI) and cold ischaemia (CI) in hearts from mouse, pig, and human. We identify common metabolic alterations during WI and those affected by CI, thereby elucidating mechanisms underlying the benefits of CI, and how WI causes damage. Succinate accumulation is a major feature within ischaemic hearts across species, and CI slows succinate generation, thereby reducing tissue damage upon reperfusion caused by the production of mitochondrial reactive oxygen species (ROS)3,4. Importantly, the inevitable periods of WI during organ procurement lead to the accumulation of damaging levels of succinate during transplantation, despite cooling organs as rapidly as possible. This damage is ameliorated by metabolic inhibitors that prevent succinate accumulation and oxidation. Our findings suggest how WI and CI contribute to transplant outcome and indicate new therapies for improving the quality of transplanted organs.

The ozone mapping and profiler suite (OMPS) is carried onboard the Suomi National Polar-orbiting Partnership satellite that was launched on October 28, 2011. The OMPS mission objectives concern atmospheric ozone concentrations and their variations in the earth atmosphere. A successful thorough on-orbit sensor calibration enabled current validated operational sensor data record (SDR) stage, providing quality sensor data that meet the requirements and users’ expectations. The calibration coefficients derived from this paper have been successfully used in a life-cycle SDR reprocessing to improve sensor data quality. In this paper, we present our qualitative analyses and the results of OMPS nadir mapper SDR on-orbit calibration, and address current SDR data quality in relation to instrument detector performance, stray light correction, and wavelength registration. Our OMPS SDR calibration experience sets a reference for the successor instruments for accurate long-term monitoring of ozone total column concentrations.

This study provides transcriptomic characterization of the cells of the crista ampullaris, sensory structures at the base of the semicircular canals that are critical for vestibular function. We performed single-cell RNA-seq on ampullae microdissected from E16, E18, P3, and P7 mice. Cluster analysis identified the hair cells, support cells and glia of the crista as well as dark cells and other nonsensory epithelial cells of the ampulla, mesenchymal cells, vascular cells, macrophages, and melanocytes. Cluster-specific expression of genes predicted their spatially restricted domains of gene expression in the crista and ampulla. Analysis of cellular proportions across developmental time showed dynamics in cellular composition. The new cell types revealed by single-cell RNA-seq could be important for understanding crista function and the markers identified in this study will enable the examination of their dynamics during development and disease.

Aims Succinate accumulates several-fold in the ischaemic heart and is then rapidly oxidized upon reperfusion, contributing to reactive oxygen species production by mitochondria. In addition, a significant amount of the accumulated succinate is released from the heart into the circulation at reperfusion, potentially activating the G-protein-coupled succinate receptor (SUCNR1). However, the factors that determine the proportion of succinate oxidation or release, and the mechanism of this release, are not known. Methods and results To address these questions, we assessed the fate of accumulated succinate upon reperfusion of anoxic cardiomyocytes, and of the ischaemic heart both ex vivo and in vivo. The release of accumulated succinate was selective and was enhanced by acidification of the intracellular milieu. Furthermore, pharmacological inhibition, or haploinsufficiency of the monocarboxylate transporter 1 (MCT1) significantly decreased succinate efflux from the reperfused heart. Conclusion Succinate release upon reperfusion of the ischaemic heart is mediated by MCT1 and is facilitated by the acidification of the myocardium during ischaemia. These findings will allow the signalling interaction between succinate released from reperfused ischaemic myocardium and SUCNR1 to be explored.

Background Ischaemia-reperfusion (IR) injury makes a major contribution to graft damage during kidney transplantation. Oxidative damage to mitochondria is an early event in IR injury. Therefore, the uptake, safety, and efficacy of the mitochondria-targeted antioxidant MitoQ were investigated in models of transplant IR injury. Methods MitoQ uptake by warm and cooled pairs of pig and declined human kidneys was measured when preserved in cold static storage or by hypothermic machine perfusion. Pairs of pigs’ kidneys were exposed to defined periods of warm and cold ischaemia, flushed and stored at 4°C with or without MitoQ (50 nmol/l to 250 µmol/l), followed by reperfusion with oxygenated autologous blood in an ex vivo normothermic perfusion (EVNP). Pairs of declined human kidneys were flushed and stored with or without MitoQ (5–100 µmol/l) at 4°C for 6 h and underwent EVNP with ABO group-matched blood. Results Stable and concentration-dependent uptake of MitoQ was demonstrated for up to 24 h in pig and human kidneys. Total blood flow and urine output were significantly greater in pig kidneys treated with 50 µmol/l MitoQ compared with controls (P = 0.006 and P = 0.007 respectively). In proof-of-concept experiments, blood flow after 1 h of EVNP was significantly greater in human kidneys treated with 50 µmol/l MitoQ than in controls (P ≤ 0.001). Total urine output was numerically higher in the 50-µmol/l MitoQ group compared with the control, but the difference did not reach statistical significance (P = 0.054). Conclusion Mitochondria-targeted antioxidant MitoQ can be administered to ischaemic kidneys simply and effectively during cold storage, and may improve outcomes after transplantation.

Many mitochondrial metabolites and bioactive molecules contain two carboxylic acid moieties that make them unable to cross biological membranes. Hence, there is considerable interest in facilitating the uptake of these molecules into cells and mitochondria to modify or report on their function. Conjugation to the triphenylphosphonium (TPP) lipophilic cation is widely used to deliver molecules selectively to mitochondria in response to the membrane potential. However, permanent attachment to the cation can disrupt the biological function of small dicarboxylates. Here, we have developed a strategy using TPP to release dicarboxylates selectively within mitochondria. For this, the dicarboxylate is attached to a TPP compound via a single ester bond, which is then cleaved by intramitochondrial esterase activity, releasing the dicarboxylate within the organelle. Leaving the second carboxylic acid free also means mitochondrial uptake is dependent on the pH gradient across the inner membrane. To assess this strategy, we synthesized a range of TPP monoesters of the model dicarboxylate, malonate. We then tested their mitochondrial accumulation and ability to deliver malonate to isolated mitochondria and to cells, in vitro and in vivo. A TPP–malonate monoester compound, TPP11–malonate, in which the dicarboxylate group was attached to the TPP compound via a hydrophobic undecyl link, was most effective at releasing malonate within mitochondria in cells and in vivo. Therefore, we have developed a TPP–monoester platform that enables the selective release of bioactive dicarboxylates within mitochondria.

Renal ischemia reperfusion (IR) injury leads to significant patient morbidity and mortality, and its amelioration is an urgent unmet clinical need. Succinate accumulates during ischemia and its oxidation by the mitochondrial enzyme succinate dehydrogenase (SDH) drives the ROS production that underlies IR injury. Consequently, compounds that inhibit SDH may have therapeutic potential against renal IR injury. Among these, the competitive SDH inhibitor malonate, administered as a cell-permeable malonate ester prodrug, has shown promise in models of cardiac IR injury, but the efficacy of malonate ester prodrugs against renal IR injury have not been investigated. Here we show that succinate accumulates during ischemia in mouse, pig and human models of renal IR injury, and that its rapid oxidation by SDH upon reperfusion drives IR injury. We then show that the malonate ester prodrug, dimethyl malonate (DMM), can ameliorate renal IR injury when administered at reperfusion but not prior to ischemia in the mouse. Finally, we show that another malonate ester prodrug, diacetoxymethyl malonate (MAM), is more potent than DMM because of its faster esterase hydrolysis. Our data show that the mitochondrial mechanisms of renal IR injury are conserved in the mouse, pig and human and that inhibition of SDH by ‘tuned’ malonate ester prodrugs, such as MAM, is a promising therapeutic strategy in the treatment of clinical renal IR injury., Graphical abstract Image 1, Highlights • Accumulation of succinate during renal ischemia is conserved across species. • Succinate dehydrogenase is a key therapeutic target in renal ischemia-reperfusion. • Malonate may inhibit succinate dehydrogenase during ischemia and on reperfusion. • Ester prodrugs enable delivery of malonate to succinate dehydrogenase in vivo. • Malonate ester prodrugs may be ‘fine-tuned’ to optimise their delivery and efficacy.

Statin-associated adverse effects, primarily muscle-related symptoms, occur in up to approximately one-third of patients in clinical practice. Recently, a Canadian Consensus Working Group outlined 6 key principles to assess and manage patients with goal-inhibiting statin intolerance, defined as a syndrome characterized by symptoms or biomarker abnormalities that prevent the long-term use of and adherence to indicated statin therapy, which includes a trial of at least 2 statins and precludes reversible causes of statin adverse effects. These principles ensure patients are appropriately receiving a statin and aware of both the benefits and risks of therapy. As well, they address factors that may increase the risk of statin-associated myopathy. A thorough assessment of patients’ clinical and laboratory history should be performed in any patient presenting with muscle symptoms on statin therapy, followed by a systematic dechallenge/rechallenge approach. In practice, most patients with statin intolerance due to muscle symptoms will be able to tolerate another statin. This is of particular importance because of the relative paucity of compelling evidence demonstrating a cardiovascular benefit with nonstatin therapies. Pharmacists are ideally situated to provide patient education, recommend changes to therapy and monitor patients with goal-inhibiting statin intolerance.

Objectives The aim of this study was to determine the prevalence of bile cast nephropathy (BCN) in autopsied cirrhotic patients and to correlate BCN with clinical and laboratory data to direct attention to this underrecognized renal complication of liver failure. Methods We assessed 114 autopsy cases of cirrhosis for the presence of renal intratubular bile casts using Hall stain for bile. Presence of bile casts was correlated with etiology of cirrhosis, clinical and laboratory data, and histologic findings. Results Bile casts were identified in 55% of cases. The most common etiology of cirrhosis was hepatitis C virus (HCV) infection (52%), and serum creatinine ( P = .02) and serum urea nitrogen ( P = .01) were significantly higher in the Hall-positive group. Conjugated bilirubin was below 20 mg/dL in 90%, and levels below 10 mg/dL were noted in 80% of cases. Conclusions To our knowledge, this is the largest study of BCN in human subjects and a first report describing the association of BCN with HCV-related cirrhosis. We demonstrated that in the face of protracted chronic hyperbilirubinemia, bile casts are formed at much lower bilirubin levels than previously thought. Furthermore, we proposed an algorithm to assist in better identification of bile casts.

Mitochondrial ROS have long been known to contribute to oxidative damage during ischemia-reperfusion (IR) injury in heart attack, stroke, and other pathological situations. Over the past few years, our work has suggested that ROS formation in IR injury was mainly coming from complex I. This led us to investigate the mechanism of the ROS production, and using a metabolomic approach, we found that the ROS production in IR injury came from the accumulation of succinate during ischemia that then drove mitochondrial ROS production by reverse electron transport at complex I during reperfusion. This surprising mechanism suggests further new therapeutic approaches to impact on the damage that mitochondrial ROS do in pathology. Here, we discuss our current understanding of how mitochondria produce ROS during IR injury.

Organoids regenerate human bile ducts Bile ducts carry bile from the liver and gall bladder to the small intestine, where it aids digestion. Cholangiocytes are epithelial cells that line bile ducts and modify bile as its transported through the biliary tree. Chronic liver diseases involving cholangiocytes account for a large fraction of liver failure and the need for liver transplantation. Because liver donors are in short supply, Sampaziotis et al. used organoid technology to develop a cell-based therapy using human tissue (see the Perspective by Kurial and Willenbring). Cholangiocyte organoids were transplanted into the intrahepatic ducts of deceased human donor livers undergoing ex vivo normothermic perfusion. The livers could be maintained for up to 100 hours, and the transplanted organoids engrafted, exhibited function, and could repair bile ducts. Science , this issue p. 839 ; see also p. 786

Single-event effects (SEE) evaluation of five different part types of next generation, commercial trench MOSFETs indicates large part-to-part variation in determining a safe operating area (SOA) for drain-source voltage ( $\text {V}_{\mathrm { {DS}}}$ ) following a test campaign that exposed >50 samples per part type to heavy ions. These results suggest a determination of a SOA using small sample sizes may fail to capture the full extent of the part-to-part variability. An example method is discussed for establishing a Safe Operating Area using a one-sided statistical tolerance limit based on the number of test samples. Burn-in is shown to be a critical factor in reducing part-to-part variation in part response. Implications for radiation qualification requirements are also explored.

A study of proton-induced destructive SEE (DSEE) from Au-plated lid fission fragments has been expanded. Seventeen additional lid materials (Z =26–83) are studied. Lead (Pb) produced a higher sensitivity than seen in previous work with gold (Au), raising new concerns of SEE enhancement due to die-proximate Pb-based solder in flip-chip package designs. New analysis has allowed generalized RHA rules to be developed.

Objectives: The issue of levamisole-adulterated cocaine is emerging as a rapidly growing public health concern due to an increasing number of reports describing its role in cutaneous vasculitis and agranulocytosis. Of note, levamisole is recognized as a contaminant in 69% of the cocaine used within the United States. Methods: We describe a patient who was a chronic cocaine user and developed systemic vasculitis characterized by polyarthralgia, bullous skin lesions, agranulocytosis, and antineutrophil cytoplasmic antibody–positive rapidly progressive glomerulonephritis. Results: The skin biopsy specimen demonstrated leukocytoclastic vasculitis. The renal biopsy specimen revealed pauci-immune necrotizing and crescentic glomerulonephritis and unusual deposits with medium electron density composed of granules, microspherules, and rare single fibrils on electron microscopy. Conclusions: The electron microscopic features of levamisole-adulterated cocaine toxicity are novel findings that are presented for the first time, to our knowledge, in this report.

The NOAA-20 Ozone Mapping Profiler Suite (OMPS) is the second Ultraviolet (UV) sensor suite in the US Joint Polar Satellite System (JPSS) program. The sensor suite was launched aboard the NOAA-20 spacecraft on Nov. 18, 2017. Like the first OMPS instrument which is flying on the Suomi National Polar-orbiting Partnership spacecraft (S-NPP), the NOAA-20 OMPS contains two advanced nadir viewing hyper-spectral instruments, the Nadir Profiler (NP) and the Nadir Mapper (NM), tracks the health of the ozone layer and measure the concentration of ozone in the Earth's atmosphere. A successful thorough early orbital calibration enabled the current provisional Sensor Data Records (SDRs) stage. We present our analyses and results of the NOAA-20 OMPS early-orbit SDR performance, demonstrate that the sensor smoothly transitioned from ground to orbit by meeting or exceeding sensor level requirements. Our results suggest that a routine calibration of dark current as well as wavelength shifts is critical in the SDR data processing.

Acute kidney injury (AKI) remains a major problem in critically unwell children and young adults. Ischaemia reperfusion (IR) injury is a major contributor to the development of AKI in a significant proportion of these cases and mitochondria are increasingly recognised as being central to this process through generation of a burst of reactive oxygen species early in reperfusion. Mitochondria have additionally been shown to have key roles in downstream processes including activation of the immune response, immunomodulation, and apoptosis and necrosis. The recognition of the central role of mitochondria in IR injury and an increased understanding of the pathophysiology that undermines these processes has resulted in identification of novel therapeutic targets and potential biomarkers. This review summarises a variety of therapeutic approaches that are currently under exploration and may have potential in ameliorating AKI in children in the future.

Proton single event dielectric rupture was observed in Analog Devices OP470 devices only when the package included gold flashing facing the die on the inner surface of the metal lid. The supply voltage was also a factor. Analysis shows that proton on gold fission fragments have the linear energy transfer and range to cause this effect. The physics of proton on gold reactions and radiation hardness assurance implications are explored.

Background: Infectious diseases consultant (IDC) pharmacists work within an IDC service to care for inpatients with complex infections. With Accreditation Canada’s new Required Organizational Practice promoting the establishment of antimicrobial stewardship (AMS) programs, AMS pharmacists are being employed in acute care hospitals. There is potential for overlap in responsibilities between IDC and AMS pharmacists, but there is no literature outlining the current duties for each group in Canada.Objective: To describe the demographic characteristics and roles of IDC and AMS pharmacists in Canadian tertiary care academic hospitals.Methods: A survey of IDC and AMS pharmacists at Canadian tertiary care academic hospitals was conducted between February and April 2015. The questionnaire included questions about the pharmacist’s experience, education, and training; the institution where the pharmacist was practising; the IDC or AMS team characteristics; and the pharmacist’s roles in clinical, educational, administrative, and research sectors.Results: The survey response rate was 77% (68/88). The 68 respondents self-identified as IDC pharmacists (14 [21%]), AMS pharmacists (34 [50%]), or dual-role IDC and AMS pharmacists (20 [29%]). Compared with AMS pharmacists, IDC pharmacists reported more of the following unique clinical activities: directly communicating with patients, attending rounds, involving patients in decision-making, and providing patient education. The 3 groups of pharmacists described similar educational responsibilities. The AMS pharmacists performed more of the following administrative and research duties: development of antibiograms and preprinted orders, collection of antimicrobial metrics, and drug-use evaluations for antimicrobials. Dual-role IDC and AMS pharmacists were involved in fewer of the unique activities described by those who practised within a single subspecialty.Conclusions: Self-identified IDC and AMS pharmacists in Canadian tertiary care academic hospitals were performing many similar roles; however, distinct differences within the clinical, administrative, and research domains were identified among IDC pharmacists, AMS pharmacists, and those who identified as dual-role IDC and AMS pharmacists.RÉSUMÉContexte : Les pharmaciens consultants en maladies infectieuses travaillent au sein d’un service de consultants en maladies infectieuses afin de prodiguer des soins aux patients hospitalisés atteints d’infections complexes. Or, en raison de la nouvelle Pratique organisationnelle requise d’Agrément Canada qui encourage la mise en oeuvre de programmes de gérance des antimicrobiens, des pharmaciens sont affectés à cette fonction dans les hôpitaux de soins de courte durée. On distingue un possible chevauchement des responsabilités entre les pharmaciens consultants en maladies infectieuses et ceux chargés de la gérance des antimicrobiens, mais il n’y a aucun document qui définit les responsabilités actuelles pour chacun de ces groupes au Canada.Objectif : Décrire les caractéristiques démographiques et les rôles des pharmaciens consultants en maladies infectieuses et de ceux chargés de la gérance des antimicrobiens dans les hôpitaux universitaires de soins tertiaires au Canada.Méthodes : Entre février et avril 2015, on a mené un sondage auprès des pharmaciens consultants en maladies infectieuses et de ceux chargés de la gérance des antimicrobiens travaillant dans les hôpitaux universitaires de soins tertiaires au Canada. Les questions portaient, entre autres, sur l’expérience du pharmacien, ses études et sa formation, l’établissement où il travaillait, les caractéristiques des équipes de consultants en maladies infectieuses et de gérance des antimicrobiens ainsi que sur ses rôles dans les secteurs cliniques et administratifs et dans les secteurs de la formation et de la recherche.Résultats : Le taux de réponse au sondage était de 77 % (68/88). Les 68 répondants s’identifiaient comme des pharmaciens consultants en maladies infectieuses (14 [21 %]), des pharmaciens chargés de la gérance des antimicrobiens (34 [50 %]) ou des pharmaciens occupant les deux rôles (20 [29 %]). Comparativement à leur collègues chargés de la gérance des antimicrobiens, les pharmaciens consultants en maladies infectieuses ont davantage indiqué accomplir les activités cliniques uniques suivantes : communiquer directement avec les patients, participer aux tournées médicales, amener les patients à participer aux prises de décisions et offrir des conseils aux patients. Les trois groupes de pharmaciens ont évoqué des responsabilités éducatives similaires. Les pharmaciens chargés de la gérance des antimicrobiens accomplissaient davantage les tâches administratives et de recherche suivantes : élaboration d’antibiogrammes et d’ordonnances préimprimées, cueillette de mesures sur les antimicrobienset évaluation de l’utilisation des antimicrobiens. Les pharmaciens qui cumulaient les deux rôles participaient à un moins grand nombre des activités uniques décrites par ceux qui exerçaient une seule sous-spécialité.Conclusions : Les pharmaciens des hôpitaux universitaires de soins tertiaires au Canada qui s’identifiaient eux-mêmes comme des pharmaciens consultants en maladies infectieuses ou des pharmaciens chargés de la gérance des antimicrobiens exécutaient bon nombre de tâches similaires. Cependant, des différences marquées en ce qui touche aux domaines clinique et administratif et à celui de la recherche ont été repérées entre les pharmaciens consultants en maladies infectieuses, ceux chargés de la gérance des antimicrobiens et ceux occupant les deux rôles.

Infectious disease and pharmacokinetic textbooks indicate that vancomycin has poor penetration into the central nervous system due to its hydrophilic nature and high molecular weight. Recent literature suggests that penetration of vancomycin into cerebrospinal fluid (CSF) is higher than previously reported; therefore, we conducted a systematic review to assess the penetration of vancomycin into CSF. We searched the MEDLINE, EMBASE, and CENTRAL electronic databases for English-language human studies evaluating serum and CSF concentrations of intravenous vancomycin. In 13 identified studies, the CSF-to-serum ratio of vancomycin varied from 0.00 to 0.81. CSF penetration ranged 0.06–0.81 in patients with meningitis, 0.05–0.17 in ventriculitis, 0.00–0.36 in other infections, and 0–0.13 in patients without infection. Despite variable CSF penetration, 83% of patients with meningitis and 100% of patients with ventriculitis achieved clinical cure. No factor predicted vancomycin CSF penetration. Contrary to prior belief, studies included in our review did not show universally low penetration of vancomycin into CSF. CSF vancomycin levels were variable and did not predict clinical cure.

The aim of this study was to determine the prevalence of bile cast nephropathy (BCN) in autopsied cirrhotic patients and to correlate BCN with clinical and laboratory data to direct attention to this underrecognized renal complication of liver failure.We assessed 114 autopsy cases of cirrhosis for the presence of renal intratubular bile casts using Hall stain for bile. Presence of bile casts was correlated with etiology of cirrhosis, clinical and laboratory data, and histologic findings.Bile casts were identified in 55% of cases. The most common etiology of cirrhosis was hepatitis C virus (HCV) infection (52%), and serum creatinine ( P = .02) and serum urea nitrogen ( P = .01) were significantly higher in the Hall-positive group. Conjugated bilirubin was below 20 mg/dL in 90%, and levels below 10 mg/dL were noted in 80% of cases.To our knowledge, this is the largest study of BCN in human subjects and a first report describing the association of BCN with HCV-related cirrhosis. We demonstrated that in the face of protracted chronic hyperbilirubinemia, bile casts are formed at much lower bilirubin levels than previously thought. Furthermore, we proposed an algorithm to assist in better identification of bile casts.

The interaction of insulin with polymeric coatings, commonly used in devices for insulin storage and administration, is affected by relative humidity (RH). Understanding the effect of RH on adhesion of insulin particles to polymeric surfaces is of particular interest for selecting coating materials and environmental conditions for packaging and storage. A custom humidity control system was constructed for use with the fluid cell cantilever holder for a Nanoscope model II atomic force microscope (AFM). This system was used for controlling the RH with a precision of ±1% over a range of ∼0–100% and for making pull-off force measurements as a function of RH. Pull-off forces were measured between insulin particles attached to the end of an AFM cantilever and acrylonitrile–butadiene–styrene and polypropylene polymers. Two critical transitions indicated by sudden increases in the pull-off force were identified at two RH values. The first transition to higher pull-off force values occurred near 15–25% RH and the ...

In this paper support vector regression is presented, and it is used to model the responses of metal oxide gas sensors to combustion byproducts. A new version of the reciprocal kernel is presented for use in the regression, and it is tested in multiple dimensions. The orthogonality of the sensors is also calculated to determine if the sensors are suitable for use in arrays. A fast numerical approximation of the sensor orthogonality, which takes advantage of the reciprocal kernel, is presented as a way of quickly optimizing the effective response of large arrays. Comparison reveals advantages over standard approaches like principal component analysis.

This paper presents an overview of the state of the National Oceanic and Atmospheric Administration (NOAA) satellite ozone programme including assessments of the current Solar Backscatter Ultraviolet (SBUV/2) and the future Ozone Mapping and Profiler Suite (OMPS) instruments and products. It provides evaluation of the quality of the NOAA Polar-orbiting Operational Satellites (POES) SBUV/2 measurements and the Version 8 algorithm products, both for operational and reprocessed data records. The presentation summarizes work on the instrument calibration and characterization; the algorithm theory and implementation; and the information content, quality and validation of the ozone estimates. This is followed by similar information on the measurements and products expected from the OMPS on the National Polar Operational Environmental Satellite System (NPOESS) and NPOESS Preparatory Project (NPP) beginning in 2011.

Nickel oxide (NiO) nanoparticles were synthesized via a solvothermal reaction with nickel(II) acetylacetonate as the metal containing precursor and 2-butanone (methyl ethyl ketone, MEK) as the solvent. The particles were characterized using X-ray diffraction, electron microscopy, Brunauer–Emmett–Teller (BET) surface area measurements and thermal gravimetric analysis (TGA) to determine that the crystal structure, particle size, and the presence of residual organic material upon completion of the reaction. The effect of varying the reaction temperature, time and metal precursor concentration were investigated. A range of optimal reaction conditions; defined here as a high yield, low residual organic content; were determined. A particle size in the range of 5.5–6.5 nm was observed for the optimal reaction conditions. The formation of metallic Ni was also observed for reactions carried out at 225 °C and time durations longer than 24 h. The reaction mechanism for the formation of NiO nanoparticles was investigated using mass spectrometry and a proposed pathway based on a keto-enol tautamerization is presented.

Twenty-one cultivars of vegetative annuals were treated with 0%, 50%, or 100% of the production fertilization rate of 300 mg·L−1 N starting 2 weeks before and continuing until harvest. At harvest, plant width, flower number, and quality rating were measured. The plants were then placed in a simulated interior environment where flower number was counted and quality rating was assigned to each plant weekly for 3 weeks. Overall, 14% of the cultivars maintained a marketable quality (i.e., quality rating of ≥3.0 of 5) for 3 weeks, 43% for 2 weeks, 38% for 1 week, and one cultivar did not maintain quality during the postharvest evaluation. Reduced end-of-production fertilization rate (EPFR) resulted in higher quality ratings for at least one additional week of simulated shelf life for three cultivars, including ‘Dreamtime Copper’ bracteantha (Bracteantha bracteata), ‘Vanilla Sachet’ nemesia (Nemesia ×hybrida), and ‘Bridal Showers’ sutera (Sutera hybrida). ‘Comet White’ and ‘Sunlight’ argyranthemum (Argyranthemum frutescens) retained flowers an additional 2 weeks and ‘Caritas Lavender’ angelonia (Angelonia angustifolia), ‘Dreamtime Copper’ bracteantha, ‘Liricashowers Deep Blue Imp.’ and ‘Starlette Trailing Purple’ calibrachoa (Calibrachoa hybrid), ‘Vanilla Sachet’ nemesia, ‘Cascadias Pink’ petunia (Petunia ×hybrida), and ‘Bridal Showers’ sutera retained flowers an additional 1 week when treated with 0% compared with 50% or 100% EPFR. Four cultivars had decreased plant width at harvest with 0% EPFR. These results indicate that reducing fertilization 2 weeks before harvest can prolong shelf life of some vegetative annuals. Differences in the length of shelf life and responses to reduced EPFR occurred among cultivars of all the affected species. Reduced EPFR did not increase the shelf life of two species, including diascia (Diascia ×hybrida) and lantana (Lantana camara).

A new solvothermal technique for synthesizing nanostructured microspheres of nickel oxide (NiO), zinc oxide (ZnO) and tricobalt tetraoxide (Co3O4) using nitrate precursors, urea and sodium dodecyl sulfate as a surfactant is described. The microspheres were shown to exhibit a morphology resembling a collection of platelets with nanoscale thickness. The surface area of the microspheres ranges from 62.8(± 0.3) to 192.9(± 1.3) m2/g, which appears to correspond to the density of platelet packing in the microsphere. The interior structure of the microspheres was investigated with a dual beam focused ion beam-scanning electron microscope and shown not to develop a hollow center.

Twenty-one cultivars from nine species of vegetative annuals were grown under optimum greenhouse production practices until maturity. At harvest, they were subjected to 0, 1, or 2 days of simulated shipping. After shipping, plants were rated for quality, and flower abscission was counted postship and weekly for 3 weeks in a simulated retail environment. There were few decreases in flower number and quality directly postship, but decline symptoms became evident as time lapsed in the postharvest environment. Flower abscission resulting from increased shipping duration occurred on ‘Sun Chimes Coral’ diascia (Diascia ×hybrida) and ‘Aromatica White’ nemesia (Nemesia ×hybrida). During the postharvest evaluation, ‘Dreamtime Copper’ bracteantha (Bracteantha bracteata), ‘Superbells Trailing Blue’ calibrachoa (Calibrachoa hybrid), ‘Aromatica White’ nemesia, and ‘Candy Floss Blue’ sutera (Sutera cordata) were the only cultivars to abscise all flowers (

Multilayer polymer films composed of a ruthenium terpyridine complex containing poly(p-phenylenevinylene) (Ru-PPV) and sulfonated polyaniline (SPAN) were prepared by a layer-by-layer electrostatic self-assembly deposition. The deposition process was carried out from SPAN solution in water and Ru-PPV in dimethylformamide (DMF). Optical-quality multilayer thin films were obtained. The film growth process was monitored by quartz crystal microbalance, and the surface morphology of the films was studied by atomic force microscopy. It was found that the properties of the multilayer films were dependent on deposition conditions such as the pH of the SPAN solution, the presence of salt in the polymer solutions, and the post-film-forming thermal annealing process. Cross-section transmission electron microscopic images suggested that there was no stratified structure formed in the multilayer films. Photovoltaic cells were fabricated by sandwiching the multilayer films between indium-tin-oxide and aluminum electrodes. The device performances were examined by illumination with AM 1.5 simulated solar light. The power conversion efficiencies of these devices were on the order of 10(-3)%. The maximum incident photon-to-electron conversion efficiency (IPCE) of the devices was found to be approximately 2% at 510 nm, which is consistent with the absorption maximum of the ruthenium complex. This indicates that the photosensitization process is due to the electronic excitation of the ruthenium complex.

An optimal protocol for stress range/number of cycles (S/N) life testing is developed. The objective is to obtain an S/N curve that will minimize the error in predictions of the service life, taking into account the fact that there is always uncertainty about an S/N curve derived from limited testing. The mathematical results apply to any problem in which there is uncertainty not only about the properties of the specimen, but also about the stress ranges that will be applied under service loads. It is shown that finding the testing procedure that will truly minimize the mean-squared error requires the solution of a quartic equation, but good approximate results can be obtained from the roots of a quadratic equation. Furthermore, it is easy to determine the consequences of using a nonoptimal testing procedure. The results are illustrated by their application to simple and commonly used models for fatigue prediction. Some numerical integration is required when the method is applied for most distributions of service stress ranges, but this is not true for the log-normal distribution and graphical results are presented which allow direct application for the popular Weibull model.

The Family Home Visit Program (FHV) is part of the year-long 1st year Practice of Medicine course, and involves local multi-generational families and students from the schools of medicine and allied health. The FHV program differs considerably from more traditional community-based clinical practice experience: visits to an ill individual, community-based experiences designed for reminiscence by the “patient,” or multiple community-based agency courses/visits. The focus of the current intergenerational FHV is on interaction between families and students in a non-clinical setting (e.g., relating to patients as “people”), learning about the social and familial context in which health and illness occur and the healthcare priorities of family members. In year 1 of the program, 200 medical students, 40 OT/PT students and 68 families participated; 204 medical students, 70 OT/PT students and 70 families participated in year 2. The development, implementation, evaluation and outcomes of the program across...

Ozone estimates from observations by the NOAA-16 Solar Backscattered Ultraviolet (SBUV/2) instrument and Television Infrared Observation Satellite (TIROS-N) Operational Vertical Sounder (TOVS) are used to describe the vertical structure of ozone in the anomalous 2002 polar vortex. The SBUV/2 total ozone maps show that the ozone hole was pushed off the Pole and split into two halves due to a split in the midstratospheric polar vortex in late September. The vortex split and the associated transport of high ozone from midlatitudes to the polar region reduced the ozone hole area from 18 × 106 km2 on 20 September to 3 × 106 km2 on 27 September 2002. A 23-yr time series of SBUV/2 daily zonal mean total ozone amounts between 70° and 80°S shows record high values [385 Dobson units (DU)] during the late-September 2002 warming event. The transport and descent of high ozone from low latitudes to high latitudes between 60 and 15 mb contributed to the unusual increase in total column ozone and a small ozone hole estimated using the standard criterion (area with total ozone < 220 DU). In contrast, TOVS observations show an ozone-depleted region between 0 and 24 km, indicating that ozone destruction was present in the elongated but unsplit vortex in the lower stratosphere. During the warming event, the low-ozone regions in the middle and upper stratosphere were not vertically aligned with the low-ozone regions in the upper troposphere and lower stratosphere. This offset in the vertical distribution of ozone resulted in higher total column ozone masking the ozone depletion in the lower stratosphere and resulting in a smaller ozone hole size estimate from satellite total ozone data.

Most medical school curricula do not equip students with adequate attitudes, knowledge and skills to care for elderly populations. We describe an effective geriatric curricular infusion model compatible with preserving the overall curricula schema. Course and clerkship directors, staff and faculty from the Office of Educational Development, Center on Aging, curriculum committee and Associate/Assistant Deans of Education, and faculty from the schools of medicine, nursing, and allied health collaborated in the effort. Each of these components and institutional financial commitment were critical to successful basic science and clinical geriatric content infusion addressing the American Geriatric Society (AGS) Core Competencies. Delivery modalities included problem-based learning cases, lectures, standardized patient portrayals for teaching and assessment, and experiential activities with elderly. Assessments were conducted and outcomes tracked in several ways, including: (1) annual course reviews, f...

The use of hybrid integration schemes is investigated using a combination of a SiOC film at the via level and a porous SiLK Y film at the trench level. Sequential finite element analysis is used to determine the mechanics and, subsequently, a hybrid damascene interconnect is built to demonstrate the approach.

Pull-off force measurements were carried out between gold-coated atomic force microscope (AFM) cantilever tips modified with self-assembled monolayers (SAMs) of thiols and similar SAMs prepared on gold-coated silicon wafer surfaces in air with a relative humidity level less than 15%. The gold sputtered silicon wafer substrate formed a granular morphology with dimensions of 30-50 nm. The radii of curvatures for the two different cantilever tips used in this study were 32 nm and 53 nm. Pull-off force results were analyzed using the Derjaguin-Muller-Toporov (DMT) contact mechanics theory to determine both surface free energy (γ) for OH, CH3, CO2H and NH2-terminated monolayers and the resultant work of adhesion (W A) between SAMs. The analysis took into account the coarse morphology of the gold coating. It was found that the γ and W A values determined with the AFM technique approached similar thermodynamic parameters as calculated from the Lifshitz-van der Waals/Lewis acid-base interaction theory using advan...

Barrier integrity of Ta-films deposited using the enhanced coverage by re-sputtering (EnCoRe) barrier was investigated on untreated surfaces of blanket porous SiLK semiconductor dielectric (developmental version 7, hereinafter v7). Barrier integrity of a bi-layer EnCoRe Ta(N)/Ta film was studied on single damascene lines using v7 and porous SiLK semiconductor dielectric (developmental version 9, hereinafter v9). On blanket wafers more than 30 nm barrier thickness is necessary to achieve complete pore sealing. Analysis of the sheet resistance showed that when tantalum is deposited, a low resistivity α-phase is nucleated on the low-k surface. When deposited onto single damascene structures, EnCoRe Ta(N)/Ta is successful in providing a continuous metallic barrier layer over v7 and v9 semiconductor dielectric lines.

A new methodology is developed that can identify the optimal testing procedure to be used in generating S-N curves for predicting damage accumulation under variable-amplitude service loads. This is a significant extension of existing knowledge, which includes a solution to this problem only for situations in which the service loads are constant amplitude. The methodology has the potential to improve significantly the predictions of fatigue damage and reliability under realistic service loads. In general, finding the truly optimal solution involves solving a quartic equation, but it is often possible to use a simplified form that involves only a quadratic equation. The new results are identical to the previously developed formulation for the special situation of a constant-amplitude service load. The information needed to use the general procedure is the distribution of stress amplitudes in the service load and the variability of the service life among identical load/specimen combinations. The procedure is illustrated here by its application to the special case of bilevel service loads, for which numerical results are presented. This includes information on both the optimal S-N testing procedure, and the sensitivity of the mean-squared error to changes in the testing procedure.

From the trend in modern medicine toward the study of genes and their contribution to the development of disease has evolved an increased awareness of ‘the diversity of genetic fingerprints among individuals’ [1]. The incorporation of this knowledge into the technologies of the pharmaceutical industry has led to the emerging field of ‘pharmacogenomics’; that is, the process of identifying the differences in genetic sequences between individuals and developing therapies [2] as ‘personal medicines’ [3]. For example, a drug used as a muscle relaxant during surgery, suxamethonium, was found to be lethal to patients who possessed a rare version of a gene involved in nerve transmission so that now those who receive this drug are tested for this specific gene [4]. Although pharmacogenomics promises great possibilities for the future of medicine, it does involve ethical and legal considerations that must be considered. Indeed, potential misuses of genetic information, such as discrimination in obtaining health insurance and in the workplace, need to be addressed. Genetic testing practices remain more advanced than the national and international laws governing the appropriate use of genetics. Although there is no national law in the United States that specifically addresses DNA and genetic privacy, several federal regulations would apply indirectly to the protection of this information and state legislators have successfully passed numerous state laws. Professional associations and private organizations have issued several guidelines for genetic testing practices. The purpose of this report is to provide a picture of the legal and ethical ramifications of genetic testing in clinical research. The genetic testing issue is presented herein in the categories of national, international, and state laws, policies, regulations and guidelines. Copyright © 2003 John Wiley & Sons, Ltd.