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Mahaim type preexcitation # Overview Mahaim type pre-excitation is a form of ventricular pre-excitation characterized by a normal PR interval and a long QRS interval with initial slurring of or slow deflection of the QRS complex (a delta wave is present). # Pathophysiology In Mahaim type pre-excitation, the atrial impulse travel to the ventricle via the Mahaim fibers which connect the atrioventricular node directly to the right ventricular wall (nodoventricular pathway) or to the right bundle branch of the His bundle (nodofascicular pathway). # Epidemiology and Demographics - Rarer than WPW or LGL # Diagnosis ## Electrocardiogram - There is a delta wave with a normal PR interval. - In older patients there can be a prolonged conduction down the accessory pathway resulting in a normal PR interval in the presence of WPW which is tough to distinguish from Mahaim fibers. Shown below is an EKG of a 24 years old man with Mahaim type of preexcitation. Shown below is an EKG of the same patient after Mahaim bundle ablation

Proximal promoter gene transcriptions The proximal sequence upstream of the gene that tends to contain primary regulatory elements is a proximal promoter. It is approximately 250 base pairs or nucleotides, nts upstream of the transcription start site. # Genetics Def. " unit of heredity; a segment of DNA or RNA that is transmitted from one generation to the next, and that carries genetic information such as the sequence of amino acids for a protein" is called a gene. The genetic information in a genome is held within genes, and the complete set of this information in an organism is called its genotype. A gene is a unit of heredity and is a region of DNA that influences a particular characteristic in an organism. Genes contain an open reading frame that can be transcribed, as well as regulatory sequences such as promoters and enhancers, which control the transcription of the open reading frame. # Promoters Def. a "section of DNA that controls the initiation of RNA transcription as a product of a gene" is called a promoter. # Proximus Def. "neighbour, nearest person or thing" is called proximus. # Theoretical proximal promoters Def. a "promoter region binds transcription factors that modify the affinity of the core promoter for RNA polymerase." is called a proximal promoter. # Distal promoters A distal promoter is a distant (in numbers of nucleotides) portion of the promoter for a particular gene. This distal sequence is upstream of the gene. It is a region of DNA that may contain additional regulatory elements, often with a weaker influence than the proximal promoter. # Dispersed promoters A dispersed promoter is a region of DNA that facilitates the transcription of a particular gene, where this promoter region contains several transcription start sites over 50-100 nucleotides. Dispersed promoters are more recent and less widespread throughout nature than focused promoters. # Focused promoters A focused promoter contains either a single transcription start site or a distinct cluster of start sites over several nucleotides. Focused promoters are sometimes referred to as narrow peak (NP) promoters. # Intermediate promoters "The intermediate transcription factor genes have early promoters, late transcription factor genes have intermediate promoters, and early transcription factor genes have late promoters, providing a cascade mechanism of regulation (4, 9, 10, 15, 22)." # Minimal promoters There is "interaction between the dominant control region (DCR) and the promoter of the human β-globin gene. Expression analysis in MEL cells has revealed that the DCR contains a number of elements capable of replacing the upstream (- 250 to - 100) erythroid-specific region of the promoter. The DCR strongly stimulates expression from a promoter possessing only a TATA box. However, this basic level of transcription is not induced upon erythroid differentiation of the cells. Mutational analysis of the minimal (- 100, noninducible) promoter shows that only the combination of the DCR and the CAC/CCAAT elements provides erythroid-specific transcription. These regions act synergistically to produce full regulated expression during erythroid differentiation." The "murine NF-E1 alone is incapable of inducing regulated expression on the minimal β-globin promoter (see ) but needs to interact with at least one ubiquitous DNA-binding protein at a neighboring site (, CP-1 at -160; deBoer et al. 1988)." "Only the minimal promoter is essential in the presence of the DCR." "The upstream part of the β-globin promoter confers inducible expression on the gene, mediated by the presence of at least one of the two NF-E1 and the (-150) CP-l-binding sites (; deBoer et al. 1988)". "Deletion analysis revealed that only the minimal part of the promoter is, in fact, sufficient for full regulated expression (, - 103). Thus, the upstream region of the promoter that contains the binding sites for the erythroid-specific transcription factor NF-E1 (see ), like the enhancers, is also made completely redundant by the DCR." # Hypotheses - At least one promoter occurs within the proximal promoter of A1BG. # Acknowledgements The content on this page was first contributed by: Henry A. Hoff. Initial content for this page in some instances came from Wikiversity.

Kringle domain Kringle Domains are autonomous protein domains that fold into large loops stabilized by 3 disulfide linkages. These are important in protein-protein interactions with blood coagulation factors. The name Kringle comes from the Scandinavian pastry that these structures resemble. Kringle domains have been found in plasminogen, hepatocyte growth factors, prothrombin, and apolipoprotein A. Kringles are found throughout the blood clotting and fibrinolytic proteins. Kringle domains are believed to play a role in binding mediators (e.g., membranes, other proteins or phospholipids), and in the regulation of proteolytic activity. Kringle domains are characterised by a triple loop, 3-disulphide bridge structure, whose conformation is defined by a number of hydrogen bonds and small pieces of anti-parallel beta-sheet. They are found in a varying number of copies in some plasma proteins including prothrombin and urokinase-type plasminogen activator, which are serine proteases belonging to MEROPS peptidase family S1A. # Human proteins containing this domain ATF; F12; F2; HABP2; HGF; HGFAC; KREMEN1; KREMEN2; LPA; LPAL2; MST1; PIK3IP1; PLAT; PLAU; PLG; PRSS12; ROR1; ROR2;

Laser diode A laser diode is a laser where the active medium is a semiconductor similar to that found in a light-emitting diode. The most common and practical type of laser diode is formed from a p-n junction and powered by injected electrical current. These devices are sometimes referred to as injection laser diodes to distinguish them from (optically) pumped laser diodes, which are more easily produced in the laboratory. # Principle of operation A laser diode, like many other semiconductor devices, is formed by doping a very thin layer on the surface of a crystal wafer. The crystal is doped to produce an n-type region and a p-type region, one above the other, resulting in a p-n junction, or diode. The many, many types of diode lasers known today collectively form a subset of the larger classification of semiconductor p-n junction diodes. Just as in any semiconductor p-n junction diode, forward electrical bias causes the two species of charge carrier, holes and electrons, to be "injected" from opposite sides of the p-n junction into the depletion region, situated at its heart. Holes are injected from the p-doped, and electrons from the n-doped, semiconductor. (A depletion region, devoid of any charge carriers, forms automatically and unavoidably as a result of the difference in chemical potential between n- and p-type semiconductors wherever they are in physical contact.) As charge injection is a distinguishing feature of diode lasers as compared to all other lasers, diode lasers are traditionally and more formally called "injection lasers." (This terminology differentiates diode lasers, e.g., from flashlamp-pumped solid state lasers, such as the ruby laser. Interestingly, whereas the term "solid-state" was extremely apt in differentiating 1950s-era semiconductor electronics from earlier generations of vacuum electronics, it would not have been adequate to convey unambiguously the unique characteristics defining 1960s-era semiconductor lasers.) When an electron and a hole are present in the same region, they may recombine or "annihilate" with the result being spontaneous emission — i.e., the electron may re-occupy the energy state of the hole, emitting a photon with energy equal to the difference between the electron and hole states involved. (In a conventional semiconductor junction diode, the energy released from the recombination of electrons and holes is carried away as phonons, i.e., lattice vibrations, rather than as photons.) Spontaneous emission gives the laser diode below lasing threshold similar properties to an LED. Spontaneous emission is necessary to initiate laser oscillation, but it is one among several sources of inefficiency once the laser is oscillating. The difference between the photon-emitting semiconductor laser (or LED) and conventional phonon-emitting (non-light-emitting) semiconductor junction diodes lies in the use of a different type of semiconductor, one whose physical and atomic structure confers the possibility for photon emission. These photon-emitting semiconductors are the so-called "direct bandgap" semiconductors. It is the nature of silicon and germanium, which are single-element semiconductors, that the bandgap does not align in such as way as to be considered "direct." However, the so-called compound semiconductors, which have virtually the identical crystal structure as silicon or germanium but use alternating arrangements of two different atomic species in a checkerboard-like pattern break the symmetry and in doing so create the critical direct bandgap. Examples of compound semiconductors are gallium arsenide, indium phosphide, gallium antimonide, gallium nitride and so forth, and junction diodes fabricated from these materials emit light. In the absence of stimulated emission (e.g., lasing) conditions, electrons and holes may coexist in proximity to one another, without recombining, for a certain time (termed the "upper-state lifetime" or "recombination time," about a nanosecond for typical diode laser materials before they recombine. Then a nearby photon with energy equal to the recombination energy can cause recombination by stimulated emission. This generates another photon of the same frequency, travelling in the same direction, with the same polarization and phase as the first photon. This means that stimulated emission causes gain in an optical wave (of the correct wavelength) in the injection region, and the gain increases as the number of electrons and holes injected across the junction increases. The spontaneous and stimulated emission processes are vastly more efficient in direct bandgap semiconductors than in indirect bandgap semiconductors, thus silicon is not a common material for laser diodes. As in other lasers, the gain region is surrounded with an optical cavity to form a laser. In the simplest form of laser diode, an optical waveguide is made on that crystal surface, such that the light is confined to a relatively narrow line. The two ends of the crystal are cleaved to form perfectly smooth, parallel edges, forming a Fabry-Perot resonator. Photons emitted into a mode of the waveguide will travel along the waveguide and be reflected several times from each end face before they are emitted. As a light wave passes through the cavity, it is amplified by stimulated emission, but light is also lost due to absorption and by incomplete reflection from the end facets. Finally, if there is more amplification than loss, the diode begins to "lase". Some important properties of laser diodes are determined by the geometry of the optical cavity. Generally, in the vertical direction, the light is contained in a very thin layer, and the structure supports only a single optical mode in the direction perpendicular to the layers. In the lateral direction, if the waveguide is wide compared to the wavelength of light, then the waveguide can support multiple lateral optical modes, and the laser is known as "multi-mode". These laterally multi-mode lasers are adequate in cases where one needs a very large amount of power, but not a small diffraction-limited beam; for example in printing, activating chemicals, or pumping other types of lasers. In applications where a small focused beam is needed, the waveguide must be made narrow, on the order of the optical wavelength. This way, only a single lateral mode is supported and one ends up with a diffraction limited beam. Such single spatial mode devices are used for optical storage, laser pointers, and fiber optics. Note that these lasers may still support multiple longitudinal modes, and thus can lase at multiple wavelengths simultaneously. The wavelength emitted is a function of the band-gap of the semiconductor and the modes of the optical cavity. In general, the maximum gain will occur for photons with energy slightly above the band-gap energy, and the modes nearest the gain peak will lase most strongly. If the diode is driven strongly enough, additional side modes may also lase. Some laser diodes, such as most visible lasers, operate at a single wavelength, but that wavelength is unstable and changes due to fluctuations in current or temperature. Due to diffraction, the beam diverges (expands) rapidly after leaving the chip, typically at 30 degrees vertically by 10 degrees laterally. A lens must be used in order to form a collimated beam like that produced by a laser pointer. If a circular beam is required, cylindrical lenses and other optics are used. For single spatial mode lasers, using symmetrical lenses, the collimated beam ends up being elliptical in shape, due to the difference in the vertical and lateral divergences. This is easily observable with a red laser pointer. The simple diode described above has been heavily modified in recent years to accommodate modern technology, resulting in a variety of types of laser diodes, as described below. # Laser diode types The simple laser diode structure, described above, is extremely inefficient. Such devices require so much power that they can only achieve pulsed operation without damage. Although historically important and easy to explain, such devices are not practical. ## Double heterostructure lasers In these devices, a layer of low bandgap material is sandwiched between two high bandgap layers. One commonly-used pair of materials is gallium arsenide (GaAs) with aluminium gallium arsenide (AlxGa(1-x)As). Each of the junctions between different bandgap materials is called a heterostructure, hence the name "double heterostructure laser" or DH laser. The kind of laser diode described in the first part of the article may be referred to as a homojunction laser, for contrast with these more popular devices. The advantage of a DH laser is that the region where free electrons and holes exist simultaneously—the active region—is confined to the thin middle layer. This means that many more of the electron-hole pairs can contribute to amplification—not so many are left out in the poorly amplifying periphery. In addition, light is reflected from the heterojunction; hence, the light is confined to the region where the amplification takes place. ## Quantum well lasers If the middle layer is made thin enough, it acts as a quantum well. This means that the vertical variation of the electron's wavefunction, and thus a component of its energy, is quantised. The efficiency of a quantum well laser is greater than that of a bulk laser because the density of states function of electrons in the quantum well system has an abrupt edge that concentrates electrons in energy states that contribute to laser action. Lasers containing more than one quantum well layer are known as multiple quantum well lasers. Multiple quantum wells improve the overlap of the gain region with the optical waveguide mode. Further improvements in the laser efficiency have also been demonstrated by reducing the quantum well layer to a quantum wire or to a "sea" of quantum dots. In a quantum cascade laser, the difference between quantum well energy levels is used for the laser transition instead of the bandgap. This enables laser action at relatively long wavelengths, which can be tuned simply by altering the thickness of the layer. ## Separate confinement heterostructure lasers The problem with the simple quantum well diode described above is that the thin layer is simply too small to effectively confine the light. To compensate, another two layers are added on, outside the first three. These layers have a lower refractive index than the centre layers, and hence confine the light effectively. Such a design is called a separate confinement heterostructure (SCH) laser diode. Almost all commercial laser diodes since the 1990s have been SCH quantum well diodes. ## Distributed feedback lasers Distributed feedback lasers (DFB) are the most common transmitter type in DWDM-systems. To stabilize the lasing wavelength, a diffraction grating is etched close to the p-n junction of the diode. This grating acts like an optical filter, causing a single wavelength to be fed back to the gain region and lase. Since the grating provides the feedback that is required for lasing, reflection from the facets is not required. Thus, at least one facet of a DFB is anti-reflection coated. The DFB laser has a stable wavelength that is set during manufacturing by the pitch of the grating, and can only be tuned slightly with temperature. Such lasers are the workhorse of demanding optical communication. ## VCSELs Vertical-cavity surface-emitting lasers (VCSELs) have the optical cavity axis along the direction of current flow rather than perpendicular to the current flow as in conventional laser diodes. The active region length is very short compared with the lateral dimensions so that the radiation emerges from the surface of the cavity rather than from its edge as shown in Fig. 2. The reflectors at the ends of the cavity are dielectric mirrors made from alternating high and low refractive index quarter-wave thick multilayer. Such dielectric mirrors provide a high degree of wavelength-selective reflectance at the required free surface wavelength λ if the thicknesses of alternating layers d1 and d2 with refractive indices n1 and n2 are such that n1d1 + n2d2 = ½λ which then leads to the constructive interference of all partially reflected waves at the interfaces. But there is a disadvantage because of the high mirror reflectivities, VCSELs have lower output powers when compared to edge emitting lasers. There are several advantages to producing VCSELs when compared with the production process of edge-emitting lasers. Edge-emitters cannot be tested until the end of the production process. If the edge-emitter does not work, whether due to bad contacts or poor material growth quality, the production time and the processing materials have been wasted. Additionally, because VCSELs emit the beam perpendicular to the active region of the laser as opposed to parallel as with an edge emitter, tens of thousands of VCSELs can be processed simultaneously on a three inch Gallium Arsenide wafer. Furthermore, even though the VCSEL production process is more labor and material intensive, the yield can be controlled to a more predictable outcome. ## VECSELs Vertical external-cavity surface-emitting lasers, or VECSELs, are similar to VCSELs. In VCSELs, the mirrors are typically grown epitaxially as part of the diode structure, or grown separately and bonded directly to the semiconductor containing the active region. VECSELs are distinguished by a construction in which one of the two mirrors is external to the diode structure. As a result, the cavity includes a free-space region. A typical distance from the diode to the external mirror would be 1 cm. One of the most interesting features of any VECSEL is the thin-ness of the semiconductor gain region in the direction of propagation, less than 100 nm. In contrast, a conventional in-plane semiconductor laser entails light propagation over distances of from 250 µm upward to 2 mm or longer. The significance of the short propagation distance is that it causes the effect of "antiguiding" nonlinearities in the diode laser gain region to be minimized. The result is a large-cross-section single-mode optical beam which is not attainable from in-plane ("edge-emitting") diode lasers. Several workers demonstrated optically pumped VECSELs, and they continue to be developed for many applications including high power sources for use in industrial machining (cutting, punching, etc.) because of their unusually high power and efficiency when pumped by multi-mode diode laser bars. Electrically pumped VECSELs have also been demonstrated. Applications for electrically pumped VECSELs include projection displays, served by frequency doubling of near-IR VECSEL emitters to produce blue and green light. # Failure modes Laser diodes have the same reliability and failure issues as light emitting diodes. In addition they are subject to catastrophic optical damage (COD) when operated at higher power. Many of the advances in reliability of diode lasers in the last 20 years remain proprietary to their developers. The reliability of a laser diode can make or break a product line. Moreover, "reverse engineering" is not always able to uncover the differences between more-reliable and less-reliable diode laser products. At the edge of a diode laser, where light is emitted, a mirror is traditionally formed by cleaving the semiconductor wafer to form a specularly reflecting plane. This approach is facilitated by the weakness of the crystallographic plane in III-V semiconductor crystals (such as GaAs, InP, GaSb, etc.) compared to other planes. A scratch made at the edge of the wafer and a slight bending force causes a nearly atomically perfect mirror-like cleavage plane to form and propagate in a straight line across the wafer. But it so happens that the atomic states at the cleavage plane are altered (compared to their bulk properties within the crystal) by the termination of the perfectly periodic lattice at that plane. Surface states at the cleaved plane, have energy levels within the (otherwise forbidden) bandgap of the semiconductor. Essentially, as a result when light propagates through the cleavage plane and transits to free space from within the semiconductor crystal, a fraction of the light energy is absorbed by the surface states whence it is converted to heat by phonon-electron interactions. This heats the cleaved mirror. In addition the mirror may heat simply because the edge of the diode laser—which is electrically pumped—is in less-than-perfect contact with the mount that provides a path for heat removal. The heating of the mirror causes the bandgap of the semiconductor to shrink in the warmer areas. The bandgap shrinkage brings more electronic band-to-band transitions into alignment with the photon energy causing yet more absorption. This is thermal runaway, a form of positive feedback, and the result can be melting of the facet, known as catastrophic optical damage, or COD. In the 1970's this problem, which is particularly nettlesome for GaAs-based lasers emitting between 1 µm and 0.630 µm wavelengths (less so for InP based lasers used for long-haul telecommunications which emit between 1.3 µm and 2 µm), was identified. Michael Ettenberg, a researcher and later Vice President at RCA Laboratories' David Sarnoff Research Center in Princeton, New Jersey, devised a solution. A thin layer of aluminum oxide was deposited on the facet. If the aluminum oxide thickness is chosen correctly it functions as an anti-reflective coating, reducing reflection at the surface. This alleviated the heating and COD at the facet. Since then, various other refinements have been employed. One approach is to create a so-called non-absorbing mirror (NAM) such that the final 10 µm or so before the light emits from the cleaved facet are rendered non-absorbing at the wavelength of interest. In the very early 1990s, SDL, Inc. began supplying high power diode lasers with good reliability characteristics. CEO Donald Scifres and CTO David Welch presented new reliability performance data at, e.g., SPIE Photonics West conferences of the era. The methods used by SDL to defeat COD were considered to be highly proprietary and have still not been disclosed publicly as of June, 2006. In the mid-1990s IBM Research (Ruschlikon, Switzerland) announced that it had devised its so-called "E2 process" which conferred extraordinary resistance to COD in GaAs-based lasers. This process, too, has never been disclosed as of June, 2006. Reliability of high-power diode laser pump bars (employed to pump solid state lasers) remains a difficult problem in a variety of applications, in spite of these proprietary advances. Indeed, the physics of diode laser failure is still being worked out and research on this subject remains active, if proprietary. Extension of the lifetime of laser diodes is critical to their continued adaptation to a wide variety of applications. # Applications of laser diodes Laser diodes are numerically the most common type of laser, with 2004 sales of approximately 733 million diode lasers, as compared to 131,000 of other types of lasers. Laser diodes find wide use in telecommunication as easily modulated and easily coupled light sources for fiber optics communication. They are used in various measuring instruments, eg. rangefinders. Another common use is in barcode readers. Visible lasers, typically red but later also green, are common as laser pointers. Both low and high-power diodes are used extensively in the printing industry both as light sources for scanning (input) of images and for very high-speed and high-resolution printing plate (output) manufacturing. Infrared and red laser diodes are common in CD players, CD-ROMs and DVD technology. Violet lasers are used in HD DVD and Blu-ray technology. Diode lasers have also found many applications in laser absorption spectrometry (LAS) for high-speed, low-cost assessment or monitoring of the concentration of various species in gas phase. High-power laser diodes are used in industrial applications such as heat treating, cladding, seam welding and for pumping other lasers, such as diode pumped solid state lasers. Applications of laser diodes can be categorized in various ways. Most applications could be served by larger solid state lasers or optical parametric oscillators, but the low cost of mass-produced diode lasers makes them essential for mass-market applications. Diode lasers can be used in a great many fields; since light has many different properties (power, wavelength & spectral quality, beam quality, polarization, etc.) it is interesting to classify applications by these basic properties. Many applications of diode lasers primarily make use of the "directed energy" property of an optical beam. In this category one might include the laser printers, bar-code readers, image scanning, illuminators, designators, optical data recording, combustion ignition, laser surgery, industrial sorting, industrial machining, and directed energy weaponry. Some of these applications are emerging while others are well-established. Applications which may today or in the future make use of the coherence of diode-laser-generated light include interferometric distance measurement, holography, coherent communications, and coherent control of chemical reactions. Applications which may make use of "narrow spectral" properties of diode lasers include range-finding, telecommunications, infra-red countermeasures, spectroscopic sensing, generation of radio-frequency or terahertz waves, atomic clock state preparation, quantum key cryptography, frequency doubling and conversion, water purification (in the UV), and photodynamic therapy (where a particular wavelength of light would cause a substance such as porphyrin to become chemically active as an anti-cancer agent only where the tissue is illuminated by light). Applications where the ability to generate ultra-short pulses of light by the technique known as "mode-locking" include clock distribution for high-performance integrated circuits, high-peak-power sources for laser-induced breakdown spectroscopy sensing, arbitrary waveform generation for radio-frequency waves, photonic sampling for analog-to-digital conversion, and optical code-division-multiple-access systems for secure communication. # History The first to demonstrate coherent light emission from a semiconductor diode (the first laser diode), is widely acknowledged to have been Robert N. Hall and his team at the General Electric research center in 1962. The first visible wavelength laser diode was demonstrated by Nick Holonyak, Jr., later in 1962 Other teams at IBM, MIT Lincoln Laboratory, Texas Instruments, and RCA Laboratories were also involved in and receive credit for historic initial demonstrations of efficient light emission and lasing in semiconductor diodes in 1962 and thereafter. In the early 1960s liquid phase epitaxy (LPE) was invented by Herbert Nelson of RCA Laboratories. By layering the highest quality crystals of varying compositions, it enabled the demonstration of the highest quality heterojunction semiconductor laser materials for many years. LPE was adopted by all the leading laboratories, worldwide and used for many years. It was finally supplanted in the 1970s by molecular beam epitaxy and organometallic chemical vapor deposition. Diode lasers of that era operated with threshold current densities of 1000 Amperes per square centimeter at 77K temperatures. Such performance enabled continuous-lasing to be demonstrated in the earliest days. However, when operated at room temperature, about 300K, threshold current densities were two orders of magnitude greater, or 100,000 Amperes per square centimeter in the best devices. The dominant challenge for the remainder of the 1960s was to obtain low threshold current density at 300K and thereby to demonstrate continuous-wave lasing at room temperature from a diode laser. The first diode lasers were homojunction diodes. That is, the material (and thus the bandgap) of the waveguide core layer and that of the surrounding clad layers, were identical. It was recognized that there was an opportunity, particularly afforded by the use of liquid phase epitaxy using aluminum gallium arsenide, to introduce heterojunctions. Heterostructures consist of layers of semiconductor crystal having varying bandgap and refractive index. Heterojunctions (formed from heterostructures) had been recognized by Herbert Kroemer, while working at RCA Laboratories in the mid-1950s, as having unique advantages for several types of electronic and optoelectronic devices including diode lasers. LPE afforded the technology of making heterojunction diode lasers. The first heterojunction diode lasers were single-heterojunction lasers. These lasers utilized aluminum gallium arsenide p-type injectors situated over n-type gallium arsenide layers grown on the substrate by LPE. An admixture of aluminum replaced gallium in the semiconductor crystal and raised the bandgap of the p-type injector over that of the n-type layers beneath. It worked; the 300K threshold currents went down by 10× to 10,000 amperes per square centimeter. Unfortunately, this was still not in the needed range and these single-heterostructure diode lasers did not function in continuous wave operation at room temperature. The innovation that broke the room temperature challenge was the double heterostructure laser. The trick was to quickly move the wafer in the LPE apparatus between different "melts" of aluminum gallium arsenide (p- and n-type) and a third melt of gallium arsenide. It had to be done rapidly since the gallium arsenide core region needed to be significantly under 1 µm in thickness. This may have been the earliest true example of "nanotechnology." The first laser diode to achieve continuous wave operation was a double heterostructure demonstrated in 1970 essentially simultaneously by Zhores Alferov and collaborators (including Dmitri Z. Garbuzov) of the Soviet Union, and Morton Panish and Izuo Hayashi working in the United States. However, it is widely accepted that Zhores I. Alferov and team reached the milestone first. For their accomplishment and that of their co-workers, Alferov and Kroemer shared the 2000 Nobel Prize in Physics.

Rifabutin adverse reactions # Adverse Reactions MYCOBUTIN Capsules were generally well tolerated in the controlled clinical trials. Discontinuation of therapy due to an adverse event was required in 16% of patients receiving MYCOBUTIN, compared to 8% of patients receiving placebo in these trials. Primary reasons for discontinuation of MYCOBUTIN were rash (4% of treated patients), gastrointestinal intolerance (3%), and neutropenia (2%). The following table enumerates adverse experiences that occurred at a frequency of 1% or greater, among the patients treated with MYCOBUTIN in studies 023 and 027. CLINICAL ADVERSE EVENTS REPORTED IN <1% OF PATIENTS WHO RECEIVED MYCOBUTIN Considering data from the 023 and 027 pivotal trials, and from other clinical studies, MYCOBUTIN appears to be a likely cause of the following adverse events which occurred in less than 1% of treated patients: flu-like syndrome, hepatitis, hemolysis, arthralgia, myositis, chest pressure or pain with dyspnea, and skin discoloration. The following adverse events have occurred in more than one patient receiving MYCOBUTIN, but an etiologic role has not been established: seizure, paresthesia, aphasia, confusion, and non-specific T wave changes on electrocardiogram. When MYCOBUTIN was administered at doses from 1050 mg/day to 2400 mg/day, generalized arthralgia and uveitis were reported. These adverse experiences abated when MYCOBUTIN was discontinued. The following table enumerates the changes in laboratory values that were considered as laboratory abnormalities in studies 023 and 027. The incidence of neutropenia in patients treated with MYCOBUTIN was significantly greater than in patients treated with placebo (p = 0.03). Although thrombocytopenia was not significantly more common among patients treated with MYCOBUTIN in these trials, MYCOBUTIN has been clearly linked to thrombocytopenia in rare cases. One patient in study 023 developed thrombotic thrombocytopenic purpura, which was attributed to MYCOBUTIN. Uveitis is rare when MYCOBUTIN is used as a single agent at 300 mg/day for prophylaxis of MAC in HIV-infected persons, even with the concomitant use of fluconazole and/or macrolide antibiotics. However, if higher doses of MYCOBUTIN are administered in combination with these agents, the incidence of uveitis is higher. Patients who developed uveitis had mild to severe symptoms that resolved after treatment with corticosteroids and/or mydriatic eye drops; in some severe cases, however, resolution of symptoms occurred after several weeks. When uveitis occurs, temporary discontinuance of MYCOBUTIN and ophthalmologic evaluation are recommended. In most mild cases, MYCOBUTIN may be restarted; however, if signs or symptoms recur, use of MYCOBUTIN should be discontinued (Morbidity and Mortality Weekly Report, September 9, 1994). Adverse reactions identified through clinical trials or post-marketing surveillance by system organ class (SOC) are listed below. ## Blood and lymphatic system disorders Pancytopenia, white blood cell disorders (including agranulocytosis, leukopenia, lymphopenia, granulocytopenia, neutropenia, white blood cell count decreased, neutrophil count decreased), thrombocytopenia, platelet count decreased, anemia. ## Immune system disorders Shock, hypersensitivity, bronchospasm, rash, eosinophilia. ## Eye disorders Uveitis, corneal deposits. ## Gastrointestinal disorders Clostridium difficile colitis, nausea, vomiting. ## Hepato-biliary disorders Jaundice, hepatic enzyme increased. ## Skin and subcutaneous tissue disorders Skin discoloration. ## Musculoskeletal and connective tissue disorders: Arthralgia, myalgia. ## General disorders and administration site conditions Pyrexia. Pyrexia, rash and rarely other hypersensitivity reactions such as eosinophilia, bronchospasm and shock might occur, as has been seen with other antibiotics. A limited number of skin discoloration has been reported. Mild to severe, reversible uveitis has been reported less frequently when MYCOBUTIN is used at 300 mg as monotherapy in MAC prophylaxis versus MYCOBUTIN in combination with clarithromycin for MAC treatment (see also Warnings). Corneal deposits have been reported during routine ophthalmologic surveillance of some HIV-positive pediatric patients receiving MYCOBUTIN as part of a multiple drug regimen for MAC prophylaxis. The deposits are tiny, almost transparent, asymptomatic peripheral and central corneal deposits, and do not impair vision.

IgG deficiency # Overview IgG deficiency is a form of hypogammaglobulinemia where the serum concentrations of one or more subclasses of IgG are diminished relative to other immunoglobulin isotypes, meanwhile total IgG concentration is noral. IgG deficiency is a laboratory finding that may be not associated with significant clinical presentations. The diagnosis of a clinically significant IgG deficiency needs evidence of antibody dysfunction in the form of recurrent infections and an inadequate response to vaccine challenge. Most patients with IgG deficiency are usually asymptomatic. Symptoms of IgG deficiency may include the symptoms of recurrent sinopulmonary infections include otitis media, rhinosinusitis, and pneumonia or even more serious infections that can occur such as osteomyelitis, meningitis, septicemia, diarrhea, and skin infections. IgG has four subclasses: IgG1, IgG2, IgG3, and IgG4. It is possible to have either a global IgG deficiency, or a deficiency of one or more specific subclasses of IgG. Since IgG1 forms about 70 percent of total IgG patients with IgG1 deficiency are classified as common variable immunodeficiency (CVID), a diagnosis that also needs reduced levels of IgA and/or IgM. IgG2 subclass deficiency is the main clinically relevant form of IgG deficiency and is more prevalent among children than adults and is one of the most frequently identified disorders in children with recurrent infections in children or may present as transient hypogammaglobulinemia of infancy (THI), and may occur with or without additional reduction in IgA or IgM. IgG3 deficiency is not usually encountered without other concomitant immunoglobulin deficiencies, and IgG4 deficiency is very common but usually asymptomatic. The diagnosis of a clinically significant IgG deficiency needs evidence of antibody dysfunction in the form of recurrent infections and an inadequate response to vaccine challenge. Management consists of immunization with conjugate vaccines in patients who have not responded to polysaccharide vaccines, aggressive treatment of other conditions predisposing to recurrent sinopulmonary infections and appropriate antibiotic therapy for infections and the use of prophylactic antibiotics for patients with repeated sinopulmonary infections. Intravenous or subcutaneous immune globulin replacement should be reserved for patients with clearly impaired responses to protein and/or polysaccharide antigens and/or if the use of prophylactic antibiotics does not cause fewer infections or in patients with persistent and symptomatic chronic rhinosinusitis . # Historical Perspective In 1952, Bruton reported a condition in an 8-year-old boy with recurrent episodes of bacterial infections and sepsis with the same serotypes of pneumococcus, while he had intact lymphoid tissue and B-cells but had decreased IgG levels and he had no antibodies against this pathogen. In the 1960s, by the discovery of the IgG subclasses, further aspects of IgG deficiency and recurrent infection, were uncovered. and thrown new light on the understanding of IgG deficiencies subclasses, as isolated deficiencies (eg, selective IgG deficiency) or in association with deficiencies of other immunoglobulin types. Moreover, how even if the total IgG concentration is normal, deficiencies of one or more individual IgG subclasses, may be observed. # Classification IgG deficiency may be classified according to individual IgG subclasses deficiency into four subtypes: - IgG1 deficiency : since IgG1 normally comprises almost two-thirds of the total serum IgG most patients with IgG1 deficiency have generalized hypogammaglobulinemia.Thus, most patients with significant IgG1 deficiency are classified as common variable immunodeficiency (CVID), a diagnosis that also requires decreased levels of IgA and/or IgM. Only patients with selective IgG1 deficiency and normal levels of total IgG should be diagnosed with IgG1 deficiency. Selective IgG1 deficiency with normal total IgG is uncommon. - IgG2 deficiency : is more prevalent among children than adults and is one of the most frequently identified disorders in children with recurrent infections.It has been described both as an isolated finding and in combination with IgG4 and/or IgA deficiency. - IgG3 deficiency : is more common in adults than children. It may occur alone or in combination with other subclass deficiencies, especially IgG1. - IgG4 deficiency : is considered to be common in the general population, meanwhile the majority of patients are asymptomatic. It may occur alone, or in combination with IgG2 deficiency, and with IgA-IgG2 deficiencies # Pathophysiology Immunodeficiency diseases are described according to involvement one or more of the 4 major components of the immune system. These components are: - B cells - T cells - phagocytes - complement B-cell or humoral immunity is mediated by the immunoglobulins. There are five types or classes of immunoglobulin: IgG, IgA, IgM, IgD, and IgE. The IgG class of antibodies is composed of four different subtypes of IgG molecules called the IgG subclasses. These are designated IgG1, IgG2, IgG3, and IgG4. The term "IgG subclass deficiency" refers to a significant decrease in the serum concentrations of one or more subclasses of IgG in a patient whose total IgG concentration is normal ## PATHOGENESIS The primary mechanisms underlying IgG subclass deficiency are unclear. Gene deletions, transcription errors, cytokine dysregulation, immunosuppressive therapy, and allotypic variations are some mechanisms that have been described : - Gene deletions: Heterozygous gene deletions cause the reduction in the serum concentration of the corresponding subclass. Deletions have been detected for genes C-gamma-1, C-gamma-2, and C-gamma-4 . Homozygous deletions of large portions of the immunoglobulin heavy chain gene, causes the absence of multiple immunoglobulin classes, and are also described. Such patients may have no detectable IgG1, IgG2, IgG4, IgA1, or IgE . - Transcription errors: Changes of germline transcription and limitation fragment length polymorphisms 5' of the S-gamma-4 loci within the gamma-chain constant region gene complex have been described among patients with IgG4 deficiency compared with controls. - Effect of allotype: Some IgG subclass deficiencies may be affected by allotype. The absence of the G2m(n) allotype and homozygosity for the G3m(g) and G3m(b) allotypes has been discoverd among Caucasian patients. # Causes - There are no established causes for IgG deficiency, and mechanisms underlying IgG subclass deficiency are unclear. Genetic, transcription errors, allotypic variations,and immunosuppressive therapy are some mechanisms that have been proposed. # Differentiating IgG deficiency from other Diseases IgG deficiency must be differentiated from other diseases that cause recurrent episodic infections, especially recurrent sinopulmonary infections including otitis media, rhinosinusitis, and pneumonia. IgG defieciency should be differentiated from other disorders leading to hypogammaglobulinemia and defects of humoral immunity. The following conditions may be considered as differentials: - Malignancy: can cause the reduction in the immunoglobulin production. - Viral infections: such as Epstein-Barr virus, HIV, cytomegalovirus are other causes of hypogammaglobulinemia. - Side effect of certain medications: Some drugs include systemic glucocorticoids, phenytoin, and carbamazepine, have been associated with IgG deficiency. - Other causes of primary humoral immunodeficiencies. - Smoking: may cause IgG2 subclass deficiency. - Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins. # Epidemiology and Demographics The prevalence of IgG deficiency is not clear. Some studies estimated that the prevalence of IgG deficiency may be 1 case per 10,000 persons.Among patient populations with more frequent or severe infections, IgG subclass deficiency is a common finding. In two large series from France, IgG subclass deficiency was reported in 20 percent of 483 patients with abnormally recurrent, prolonged, or severe infection; IgG3 was the most common deficiency. In a report of 1175 adults with symptoms suggestive of an antibody deficiency, decreased IgG1, IgG2, IgG3, and IgG4 levels were reported in 28, 17, 13, and 9 percent, respectively. ## Age - IgG deficiency can affect both children and adults. The most common subclass deficiency in early childhood is IgG2 deficiency; in adults, IgG1 and IgG3 deficiencies predominate. In children, IgG1 deficiency accounts for higher cases of the total IgG deficiency in comparison to adults. even though children reach the adult levels of IgG1 and IgG3, but the development of IgG2 and IgG4 is slower. In some children, maturation of IgG subclasses may be delayed until the adolescence. ## Gender - The gender prevalance of IgG deficiency differs in children and adults. In children, IgG deficiency is more common in boys by a ratio of 3:1. In contrast, there is a predominance of females after age 16. This shift in gender distribution may be owing to hormonal influences upon the immune system. ## Race - There is no racial predilection for IgG deficiency. # Risk Factors Common risk factors in the development of IgG deficiency: - Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins. - Intense exercise or excessive physical stress - Smoking - Aging # Natural History, Complications and Prognosis Natural History - The majority of patients with IgG deficiency remain asymptomatic. In addition, there are patients with complete deficiencies of multiple combinations of IgG1, IgG2, IgG4, IgE, or IgA deficiency who remain healthy and free of infections. Complications - Common complications of IgG deficiency include bronchiectasis, bronchiolitis obliterans , interstitial lung disease , mediastinal and/or hilar adenopathy, and malignancy. Prognosis - Prognosis is mainly affected by the degree of deficiency as well as the age of the patient. Evidence suggests that the majority of children younger than eight years of age with IgG subclass deficiency will normalize IgG subclass level. - Adults with clinically notable IgG subclass deficiency and diminished particular antibody responses will scarcely reach previous normal level of a deficient IgG subclass. # Diagnosis ## Diagnostic Criteria IgG deficiency is a laboratory finding that may be not associated with significant clinical presentations. The diagnosis of a clinically significant IgG deficiency needs evidence of antibody dysfunction in the form of recurrent infections and an inadequate response to vaccine challenge. The diagnosis of IgG deficiency required the following two diagnostic criteria to meet in the clinical history of recurrent sinopulmonary infections: - low IgG subclass levels - poor antibody response to the vaccine challenge ## Symptoms - IgG deficiency is usually asymptomatic. - Symptoms of IgG deficiency may include the symptoms of recurrent sinopulmonary infections include otitis media, rhinosinusitis, and pneumonia or even more serious infections that can occur such as osteomyelitis, meningitis, septicemia, diarrhea, and various skin infections. ## Physical Examination - Physical examination of patients with longstanding immune defects may be remarkable for: - Low body mass index - Scarring of tympanic membranes or skin - Signs of chronic lung disease such as chronic cough, absent gag reflex, clubbing, crackles, or wheezing to suggest bronchiectasis - Ongoing infection signs of chronic sinusitis, oral thrush, warts, or dermatophyte infections ## Laboratory Findings - IgG deficiency is a laboratory finding that may be not associated with significant clinical presentations. The normal amounts for IgG subclasses are wide and differ with the age of the patients. For children 4 to 10 years of age, levels below the following are considered abnormal: - IgG1 level <250 mg/dL - IgG2 level <50 mg/dL - IgG3 level <15 mg/dL - IgG4 level <1 mg/dL For individuals older than 10 years of age, levels below the following are considered abnormal: - IgG1 level <300 mg/dL - IgG2 level <50 mg/dL - IgG3 level <25 mg/dL - IgG4 level <1 mg/dL ## Vaccine Challenge Response IgG subclass deficiency is a laboratory finding which does not necessarily cause clinical presentations. For final diagnosis of IgG subclass deficiency, patients must be evaluated for antibody dysfunction in both polysaccharides and proteins antigens. The function can be assessed by measuring antibody titers to previously administered vaccines or natural infections. If titers are not in the protective range, a vaccine challenge should be performed with the administration of vaccines with measurement of pre- and postimmunization titers Titers of IgG antibodies to tetanus and diphtheria in vaccinated children and adults are used to evaluate immune responsiveness to protein antigens. Results are reported as IgG in general, although the antibody responses generated by these vaccines are largely (but not exclusively) composed of IgG1 and IgG3 antibodies, which is sometimes important in the evaluation of IgG subclass deficiency. Interpretation of Hib titers — The capsular polysaccharide polyribosylribitol phosphate (PRP) is an important antigen in immunity to Haemophilus influenzae type B (Hib). Anti-PRP IgG titers ≥1 mcg/mL are considered protective . Although the polysaccharide PRP is the primary antigen, the conjugate vaccines employ either diphtheria toxoid or the outer membrane protein complex of meningococcus as the immunogenic protein. Therefore, antibodies to the Hib capsular polysaccharide in patients who received the conjugated Hib vaccine reflect a protein response, and protective antibodies against the PRP polysaccharide do not exclude unresponsiveness to the pure pneumococcal polysaccharides. Children in the United States have been receiving conjugated vaccines for prophylaxis against Hib since the early 1990s. # Treatment ## Medical Therapy The mainstay of therapy for IgG deficiency includes the following : - Immunization with conjugate vaccines in patients who have not responded to polysaccharide vaccines - Aggressive management of asthma, allergic rhinitis predisposing to recurrent sinopulmonary infections - Recognition and treatment of sinopulmonary bacterial infections since infections are less likely to clear spontaneously in patients with antibody defects. - Prophylactic antibiotics for patients with recurrent sinopulmonary infections. Evidence in support of this approach is largely derived from benefits observed in retrospective studies of children with this and similar antibody deficiencies. - Intravenous or subcutaneous immune globulin replacement is indicated if the use of prophylactic antibiotics does not cause fewer infections or in patients with persistent and symptomatic chronic rhinosinusitis. This therapy should be reserved for patients with clearly impaired responses to protein and/or polysaccharide antigens. - Intravenous immune globulin therapy, at a standard dose range of 400 to 600 mg/kg, can be infused every three to four weeks. Immune globulin can also be replaced subcutaneously at weekly intervals. - Immune globulin therapy should be administered for one to two years initially, at which point the patient's status should be re-evaluated to determine if the number and/or severity of infections have been reduced. Not all patients with IgG subclass deficiencies benefit from immune globulin replacement, and the therapy should be discontinued if not effective in that individual. ## Prevention - There are no primary preventive measures available for IgG deficiency. - Secondary and tertiary prevention strategies following IgG deficiency include avoidance measures, vaccination, prophylactic antibiotics, immune globulin therapy,and when infections do occur, broader spectrum and more prolonged antibiotics are often recommended. - Avoidance: to reduce exposure to others with potentially contagious illnesses: proper handwashing and use of alcohol-based disinfectants should be provided to patients and their families; Co-sleeping among family members should be minimized, and immunization of family members and close contacts - Careful attention should be paid to patient's oral hygiene and dental health. - Vaccination Immunization with conjugate vaccines in patients who have not responded to polysaccharide vaccines Advisory Committee on Immunization Practices (ACIP) - Recommended that conjugated Hib vaccine be administered in patients with IgG2 subclass deficiency and those with specific antibody deficiency (SAD) - Antimicrobial therapy: Treating acute infections and prophylactic antimicrobial therapy among patients with recurrent sinopulmonary infections or ongoing lung disease is helpful. Thus, immediate recognition and treatment with antibiotics can help prevent chronic infections and infectious complications. It is important to ensure that the infection has treated completely at the end of a course of antibiotics, as patients with immunodeficiency sometimes necessitate longer durations of therapy. Antibiotic resistance does not seem to be a serious problem in patients with primary immunodeficiency, for causes which are not clearly understood, then the same antibiotics continue to be useful, regardless of prolonged or frequent exposure.

Concha bullosa # Overview Concha Bullosa is an abnormal pneumatization of the middle turbinate which may interfere with normal ventilation of sinus ostia and can result in recurrent sinusitis. As explained by doctors, "Concha bullosa refers to an enlargement or ballooning of the nasal turbinate (which is a normal structure in the nose). Concha bullosa is a normal anatomic variant, but occasionally, a concha bullosa can be very large and contribute to sinus obstruction. In these cases, the concha bullosa can be readily reduced by surgery." Concha refers to the turbinate in this case, the middle turbinate. Bullosa refers to a bubble-like structure. A middle turbinate which has an air cell in it is a concha bullosa. When these are large, they can cause nasal obstruction or facial pressure or blockage of the sinus outflow tracts. They are easily reduced with endoscopic sinus surgery. Left concha bullosa # Types of Concha Bullosa Concha bullosa (CB) is the pneumatization of the concha and is one of the most common variations of the sinonasal anatomy. A 14%-53.6% frequency of concha bullosa was reported by various studies (1). Pneumatization of the concha, regardless of the amount and the location, was defined as concha bullosa (2). Bolger et al. have classified pneumatization of the concha based on the location as lamellar concha bullosa (LCB), bulbous concha bullosa (BCB) and extensive concha bullosa (ECB) (3) # Conclusion Concha bullosa is a common anatomic variant. There is a strong association between the presence of a concha bullosa and contralateral deviation of the nasal septum. Nasal septal deviation away from the dominant concha, with preserved adjacent air channels, suggests that the deviation is not a direct result of mass effect from the concha. No increased incidence of paranasal sinus disease exists in patients with concha bullosa.

The Lancet # Overview The Lancet is one of the oldest peer-reviewed medical journals in the world, published weekly by Elsevier, part of Reed Elsevier. It was founded in 1823 by Thomas Wakley, who named it after the surgical instrument called a lancet, as well as an arched window ("to let in light"). The present editor-in-chief is Richard Horton. The Lancet takes a stand on several important medical issues - recent examples include criticism of the World Health Organization, rejecting the efficacy of homeopathy as a therapeutic option and its disapproval of Reed Elsevier's links with the arms industry. # Impact The Lancet has a significant readership throughout the world with a high impact factor. It publishes original research articles, review articles ("seminars" and "reviews"), editorials, book reviews, correspondences, amidst other regulars such as news features and case reports. The Lancet is considered to be one of the "core" general medical journals, the others being the New England Journal of Medicine, the Journal of the American Medical Association, and the British Medical Journal. The Lancet's impact factor is currently ranked #2 among general medical journals (click here for impact factor rankings). # Journals family The Lancet has now given birth to a few sub-speciality journals, all bearing the parent title - The Lancet Neurology (neurology), The Lancet Oncology (oncology) and The Lancet Infectious Diseases (infectious diseases). All of them have established significant reputations as medical journals, though most started out publishing only review articles. # Volume renumbering Prior to 1990, Lancet had volume numbering that reset every year. Issues in January to June were in volume i, with the rest in volume ii. In 1990, Lancet moved to a sequential volume numbering scheme, with two volumes per year. Volumes were retro-actively assigned to the years prior to 1990, with the first issue of 1990 being assigned volume 335, and the last issue of 1989 assigned volume 334. The table of contents listing on Science Direct uses this new numbering scheme. # Controversial articles The Lancet was severely criticized after it published a paper in 1998, in which the authors linked the MMR vaccine with autism. In February 2004 The Lancet published a partial retraction of the paper (Lancet 2004;363:750). Dr Horton went on the record to say the paper had "fatal conflicts of interest" because one of the authors had a serious conflict of interest that he had not declared to The Lancet . The Lancet published a controversial estimate of the Iraq war's Iraqi death toll--around one hundred thousand--in 2004. In 2006 a followup study by the same team suggested that the violent death rate in Iraq was not only consistent with the earlier estimate, but had increased considerably in the intervening period (Lancet surveys of mortality before and after the 2003 invasion of Iraq). The second survey estimated that there had been 654,965 excess Iraqi deaths as a consequence of the war. The 95% confidence interval was 392,979 to 942,636. 1849 households that contained 12,801 people were surveyed. In January 2006, it was revealed that data had been fabricated in an article by the Norwegian cancer researcher Jon Sudbø and 13 co-authors published in The Lancet in October 2005 . The fabricated article was entitled "Non-steroidal anti-inflammatory drugs and the risk of oral cancer: a nested case-control study". . Within a week after this scandal surfaced in the news, the high-impact New England Journal of Medicine published an expression of editorial concern regarding another research paper published on a similar topic in the journal.

EAES Recommendations for Recovery Plan in Minimally Invasive Surgery Amid COVID-19 Pandemic Background COVID-19 pandemic presented an unexpected challenge for the surgical community in general and Minimally Invasive Surgery (MIS) specialists in particular. This document aims to summarize recent evidence and experts' opinion and formulate recommendations to guide the surgical community on how to best organize the recovery plan for surgical activity across different sub-specialities after the COVID-19 pandemic. Methods Recommendations were developed through a Delphi process for establishment of expert consensus. Domain topics were formulated and subsequently subdivided into questions pertinent to different surgical specialities following the COVID-19 crisis. Sixty-five experts from 24 countries, representing the entire EAES board, were invited. Fifty clinicians and six engineers accepted the invitation and drafted statements based on specific key questions. Anonymous voting on the statements was performed until consensus was achieved, defined by at least 70% agreement. Results A total of 92 consensus statements were formulated with regard to safe resumption of surgery across eight domains, addressing general surgery, upper GI, lower GI, bariatrics, endocrine, HPB, abdominal wall and technology/research. The statements addressed elective and emergency services across all subspecialties with specific attention to the role of MIS during the recovery plan. Eighty-four of the statements were approved during the first round of Delphi voting (91.3%) and another 8 during the following round after substantial modification, resulting in a 100% consensus. Conclusion The recommendations formulated by the EAES board establish a framework for resumption of surgery following COVID-19 pandemic with particular focus on the role of MIS across surgical specialities. The statements have the potential for wide application in the clinical setting, education activities and research work across different healthcare systems. whereas many may not have been based on research evidence [bib_ref] The risk of COVID-19 transmission by laparoscopic smoke may be lower than..., Mintz [/bib_ref] [bib_ref] Current evidence for minimally invasive surgery during the COVID-19 pandemic and risk..., Chadi [/bib_ref] [bib_ref] Recommendations of the Brazilian College of Surgeons for laparoscopic surgery during the..., Ramos [/bib_ref] [bib_ref] Agresta F Acute cholecystitis during COVID-19 pandemic: a multisocietary position statement, Campanile [/bib_ref]. Preliminary guidelines recommended against performing laparoscopic surgery to avoid putative risks of SARS-CoV2 transmission via aerosolization due to pneumoperitoneum but were later revised recommending laparoscopic surgery under restrictions. Several subsequent guidelines did not recommend against laparoscopic surgery; however, they advised strict precautions such as closed circuit smoke evacuation and the use of filtering system and personal protective equipment (PPE) [bib_ref] SAGES and EAES recommendations for minimally invasive surgery during COVID-19 pandemic, Francis [/bib_ref] [bib_ref] International guidelines and recommendations for surgery during Covid-19 pandemic: a systematic review, Moletta [/bib_ref] [bib_ref] ELSA recommendations for minimally invasive surgery during a community spread pandemic: a..., Shabbir [/bib_ref]. The role of MIS has been argued to be more favourable in SARS-CoV-2 positive patients, as the potential benefits of MIS might exceed the risk of pneumoperitoneum on cardiovascular and respiratory systems [bib_ref] Minimally Invasive Surgery is the Key to Patient and Operating room team..., Mintz [/bib_ref]. Furthermore, there is substantial uncertainty with regard to specific questions related to laparoscopic procedures, and structured guidance pertinent to MIS procedures is lacking. There is an urgent need for practice-based recommendations in specific clinical situations with regard to safety precautions for patients and staff amidst the COVID-19 pandemic [bib_ref] Global guidance for surgical care during the COVID-19 pandemic, Collaborative [/bib_ref]. The purpose of this EAES initiative was to generate an updated and comprehensive set of management recommendations for MIS for each subspeciality of general surgery. This consensus was also designed to document the broader experts' opinion on how to optimize the use of human and institutional resources including the use of MIS techniques for patient benefit. # Methods A steering group (SG) was formed comprising of six experts from the EAES Executive Board (AA, NF, YM, SM, DP and AP) who organized the project and guided the data synthesis. IRB approval and informed written consent were not required. The steps of the consensus process are outlined below. ## Identification of domains and formulation of questions The clinical questions were divided into eight domains: (i) general (ii) Hepatobiliary & Pancreatic (HPB), (iii) Bariatrics (B), (iv) Abdominal Wall (AW), (v) Endocrine (E), (vi) Upper Gastrointestinal (UGI), (vii) Lower Gastrointestinal (LGI), (viii) technology and research. Domains (ii) to (vii) were divided into two subdomains: emergency and elective. ## Identification of experts to address questions Fifty-Five out of EAES board members accepted the task to contribute to this project and were divided into eight subgroups organized by the domain topics and led by a designated chair [fig_ref] Table 1: Expert group members and topic allocations [/fig_ref]. In addition, key stakeholders were invited to provide expert input into the multidisciplinary aspects of this project including anaesthesiology, radiology and oncology and were allocated to a relevant group, based on their expertise. ## Search methods and inclusion criteria Based on the research questions, a literature search was designed and performed by two independent EAES experts (AA, NF). The PubMed and Embase databases were queried for articles published before May 10th, 2020. Inclusion criteria were systematic and narrative reviews, commentaries, randomized clinical trials, cohort studies and case series on the subject of surgery during the COVID-19 and other pandemic published in the English language. Search syntaxes used was (COVID OR 'SARS CoV 2′ OR coronavirus AND surgery). ## Formulation of questions and statements Questions were drafted and submitted to the steering group, which approved them prior to sending them to the subgroups to formulate statements in response to these questions. Statements were generated by each subgroup in each topic question of their domain. Each group was advised to include any available evidence to support their statements and when evidence was not available, experts' opinion was considered. Each group conducted a literature research and drafted statements and recommendations in response to their research questions. The literature review was reported in accordance with PRISMA statement standards for systematic reviews and meta-analyses [bib_ref] Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement, Moher [/bib_ref]. Statements were then submitted to the steering group (SG) who did not participate in the formulation of these statements or in the voting process. After structural editing by the SG group, all questions were unanimously approved by all experts [fig_ref] Table 1: Expert group members and topic allocations [/fig_ref]. ## Voting and data analysis The statements received from each subgroup of experts was compiled by the SG and a modified Delphi methodology process was followed to reach agreement among all the experts on all statements and recommendations [bib_ref] Diagnosis and management of acute appendicitis. EAES consensus development conference, Gorter [/bib_ref]. EAES board members voted to declare agreement or disagreement with the statements using closed-ended questions (agree or disagree), whereas there was an option to submit free text comments. The Delphi process was implemented through the SurveyMonkey electronic platform (https ://nl.surve ymonk ey.com). To reduce the possibility of bias among participants, the authors of the statements and the resultant votes/comments remained anonymous. Each statement was subjected to live voting by all experts including key stakeholders and excluding the steering committee. Consensus was achieved when a statement reached at least 70% expert agreement. Statements with less than 70% agreement in the first round were returned to the expert subgroup who modified them according to the comments. The subgroups had the option to revise statements based on feedback for further voting. The results of the consensus are summarized using descriptive statistics. The manuscript was then drafted with the recommendations following completion of all voting and statement formulation and sent to all members for revision, input and approval prior to submission for publication. # Results Ninety-two statements were generated by the subgroups across the eight topics. The full text literature analyses and references used to generate statements and recommendations for all topics are included as Appendix 1. Eighty-four out of 92 statements (91%) were approved in the first round and further 8 modified statements were approved in the second round. Overall, the Delphi process approved 92 statements (100%) for the consensus guidelines. The questions, final recommendations and respective approval rates in each step of the Delphi processes are summarized in [fig_ref] Table 2: Questions and statements Role of a non-operative approach [/fig_ref]. Initial disagreement was regarded priorities depending on local resources, the use of energy dissection devices and the risk of aerosolization, the indication for stenting for obstructed colorectal cancer, the indication of laparoscopic lavage for diverticular disease, the indication of neoadjuvant treatment for early rectal cancer in order to postpone surgery, the management of undiagnosed pancreatic lesions, the indication for intragastric balloons to postpone bariatric surgery and the indication for endoscopic therapies for achalasia and reflux disease to postpone surgery. # Discussion The study achieved its objective of formulating EAES evidence-based recommendations to provide guidance on the resumption of MIS across various general surgery specialities, taking into account the serious burden on our healthcare systems caused by the COVID-19 pandemic. These statements provided descriptive safety guidance measures that should be undertaken in the recovery plan for elective and emergency surgery across all subspecialties with specific measures for MIS. In a recent survey, over 28 million patients are awaiting treatment worldwide, a number which continues to grow in the setting of new restrictions on delivery of care and a pandemic that is still evolving [bib_ref] Elective surgery cancellations due to the COVID-19 pandemic: global predictive modelling to..., Nepogodiev [/bib_ref]. As this progression is expected to continue, and given the uncertainty about the ongoing pandemic, adaptive changes are required in procedure-based specialties to include safety, logistic, service relocation, economic and ethical considerations [bib_ref] Immediate and longterm impact of the COVID-19 pandemic on delivery of surgical..., Søreide [/bib_ref] [bib_ref] Fair allocation of scarce medical resources in the time of Covid-19, Emanuel [/bib_ref] [bib_ref] COVID-19 pandemic: perspectives on an unfolding crisis, Spinelli [/bib_ref] [bib_ref] Surgical challenges and research priorities in the era of the COVID-19 pandemic:..., Milone [/bib_ref]. Through this project, consensus was achieved on all the proposed statements by the expert across the different domains, providing specific guidance on how to safely resume MIS and implement adaptive changes in procedure specific manner. This project adhered to Delphi principles dictating anonymous voting. The selection of the steering group and the domains chairs was based on their peers' recommendations and their leadership positions across different specialties and of their expertise on the research methodology of consensus development. The steering group did not contribute to the voting process. The Delphi design allowed us to elicit the opinion of the EAES board members along with additional key stake holders to complement the multidisciplinary and heterogeneous nature of the international panel of experts. Although evidence synthesis was part of this project to generate evidencebased recommendations, there was no found evidence that can inform the statements, hence, relied on expert opinion. A limited number of areas of continuing controversy were identified at the first voting round with lack of consensus among members. Initial disagreement was encountered on how to prioritize surgery, but ultimately total agreement was achieved by recommending that decisions should be based on local resources, the regional control of the COVID-19 pandemic and the patients' medical condition. This was fundamental in deciding priorities also hereinafter for the rest of the consensus, but it is probably an area that requires fundamental research in the immediate future. While there was also general agreement on the need to screen all patients undergoing surgery under general anaesthesia, by Reverse Transcription Polymerase Chain Reaction (RT-PCR) or even by computer tomography (CT) or ultrasound (US) lung scan in symptomatic patients, the option of regional anaesthesia should always be considered in suspected or positive patients for whom surgery cannot be postponed. Elective oncologic surgery should be only offered to SARS-CoV-2 negative patients or to previously positive patients after conversion to a negative RT-PCR COVID-19 test. One of the main objectives of this project was to clarify the role of MIS, considering the conflicting information from different guidelines. This was based on the theoretical risk of possible contamination due to aerosolization and the gas leaks demonstrated during laparoscopy [bib_ref] Laparoscopic pneumoperitoneum escape and contamination during surgery using the airseal insufflation system:..., Dalli [/bib_ref] [bib_ref] Carbon dioxide gas leaks during transanal minimally invasive surgery, Khan [/bib_ref] [bib_ref] Gas aerosol jetstreams from trocars during laparoscopic surgery-a video vignette, Khan [/bib_ref]. Until high-level evidence will be available to provide an answer about the direct link between SARS-CoV-2 contamination by pneumoperitoneum and its contagion to the operating team, the application of MIS across all surgical specialities has been supported by the experts in this project, provided local expertise is available and safety procedures are adhered to. Additionally, there was wide agreement that the general preference for MIS according to guidelines should not depend on the SARS-CoV-2 status or the indication of surgery in terms of elective and emergency settings. These precautions are in line with the recent EAES/ SAGES recommendations to reduce gas leaks [bib_ref] 2020) the Technology Committee of the European Association for Endoscopic Surgery A..., Mintz [/bib_ref] , the generation of smoke and by the use of surgical smoke evacuating systems [bib_ref] SAGES and EAES recommendations for minimally invasive surgery during COVID-19 pandemic, Francis [/bib_ref]. These guidelines are also supported by the argument that containing potentially contaminated gas within a defined space, as it happens during laparoscopy, should provide a better control of risk, when compared to open surgery [bib_ref] The risk of COVID-19 transmission by laparoscopic smoke may be lower than..., Mintz [/bib_ref]. Regardless to the mode of surgery, limiting the use of energy devices in SARS-CoV-2 positive patients was also recommended and favouring ligatures/clips and/or stapling devices when possible. This is also in line with other recommendations (EAES/SAGES) and with evidence suggesting gas escape through trocars [bib_ref] Surgical challenges and research priorities in the era of the COVID-19 pandemic:..., Milone [/bib_ref] [bib_ref] Laparoscopic pneumoperitoneum escape and contamination during surgery using the airseal insufflation system:..., Dalli [/bib_ref] [bib_ref] Carbon dioxide gas leaks during transanal minimally invasive surgery, Khan [/bib_ref]. General recommendations for personnel safety in the OR including characteristics of the environment and PPE were also confirmed [bib_ref] SAGES and EAES recommendations for minimally invasive surgery during COVID-19 pandemic, Francis [/bib_ref]. In the emergency setting, a number of recommendations were proposed by the experts, supporting conservative treatment for abscesses and collections in SARS-CoV-2 positive patients, rather than offering immediate surgery, if the general condition of patients allows this. On the contrary, for acute cholecystitis in SARS-CoV-2 positive patients, cholecystectomy was recommended when not responsive within 24 h rather than interventional treatment such as percutaneous transhepatic drainage, with the exception of ASA 3 and 4 patients. In the field of abdominal wall surgery, laparoscopy was recommended for incarcerated ventral and inguinal hernia if not otherwise contraindicated and should not be postponed if clinically indicated. Emergency endoscopy (diagnostic and therapeutic) was supported in SARS-CoV-2 positive patients, as the first line to assess and possibly to treat bleeding, neoplastic obstruction, perforation and anastomotic leak. Similarly, laparoscopic surgery should be considered after failure of conservative/endoscopic management in symptomatic patients, as well as the in acute diverticulitis management according to the accepted algorithms. Elective surgery for both malignant and benign disease should be postponed in SARS-CoV-2 positive patients until they return negative. This is also the case for hepatobiliary and pancreatic non-neoplastic diseases, as well as other oncologic patients, in whom interim procedures should be offered instead. For instance, drainage of the biliary tract by Percutaneous Transhepatic Biliary Drainage (PTBD) or Endoscopic Retrograde Cholangio Pancreatography (ERCP) should be considered as a bridging therapy. In the field of bariatric surgery, the expert group in this project supported postposing elective surgery until the recovery plan, and flexible endoscopic procedures such as intragastric balloons was recommended as a bridge to surgery during the COVID-19 pandemic. Elective laparoscopic treatment for ventral and inguinal hernia in SARS-CoV-2 negative patients may need to be postponed depending on the local situation. Endocrine surgery should only be cancelled in SARS-CoV-2 positive patients until they convert to negative. Otherwise, patients should be prioritized depending on symptoms and oncological risk. For upper and lower gastrointestinal cancer, neoadjuvant therapy could be considered for early cancers in order to postpone surgery after the COVID-19 pandemic, but only within registered studies, although difficult to arrange in short time. Functional disorders such as achalasia and reflux disease should be treated as usual and surgery can be considered if not responding to conservative treatment. The experts recommend that surgery should be delayed only in SARS-CoV-2 positive patients. Similarly, elective surgical treatment of benign colorectal pathologies should be prioritized based on patient and disease characteristics, local COVID-19 burden and institutional and staff resources. If not otherwise contraindicated, colorectal resections should be completed with anastomosis, while stoma formation should be applied as usual only for high-risk patients. Particular attention should be paid when Transanal Endoscopic Microsurgery (TEMS) or TransAnal Minimally Invasive Surgery (TAMIS) procedures are indicated, including TransAnal Total Mesorectal Excision (TaTME), due to the particularly high risk of operator contamination. In fact, alternative strategies for low rectal lesions, such as endoscopic mucosal resection and endoscopic submucosal dissection, should be considered in SARS-CoV-2 positive. On the other hand, due to its well proved benefits, a minimally invasive approach should be considered to treat colorectal cancer as well as benign conditions such as inflammatory bowel diseases and recurrent diverticulitis. Finally, we focused on technology, education and research in the time of pandemic. The team of experts outlined how research activity on digital technology and robotics should be encouraged to focus on reducing the numbers of working personnel in wards, intensive care unit and the operating rooms. In fact, this pandemic highlighted the importance of technology advancement in remote teaching and mentorship. Innovative solutions for training such as video-based education in combination with box trainers should be promoted to mitigate the restrictions of face-to-face teaching. The experts outlined certain areas of further research targeting robotics, Artificial Intelligence, advanced imaging and energy devices that could have a positive impact in times of pandemic and restrictions due to social distancing. At the same time practical technological solutions including sustainable materials and steam sterizilation for PPE should be investigated in order to minimize production of waste. Overall, this project highlighted interesting trends and controversies related to surgeons' willingness to overcome this difficult time, but it holds a number of limitations. There is a lack of empirical data to support many of the underlying statements, hence weaknesses inherent to these guidelines include the reliance on expert opinion and discussion to formulate recommendations. Despite the limited evidence, this project highlighted a number of clinically relevant questions that provide an agenda to stimulate future research in this field. The selection of experts is another critical aspect within consensus statements development. The expert group involved in this research were all the EAES board members representing the research, technology and educational committees as well as the members of the executive committee of the society. The response rate among the participants was high across the entire process reflecting the hard work and commitment of the board members to undertake this project and complete the project in a timely manner given the urgency and the need for the guidelines. # Conclusion The recommendations formulated by the EAES board create a framework for resumption of surgery following COVID-19 pandemic with particular focus on the role of MIS across all specialities. The statements have the potential for wide application in clinical setting, education and research across different healthcare systems. provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. [table] Table 1: Expert group members and topic allocations [/table] [table] Table 2: Questions and statements Role of a non-operative approach (transhepatic drainage) in cholecystitis c. Role of a Laparo-Endoscopic Rendez-Vous (LERV) approach (orotracheal intubation) in Jaundice for CBD obstruction d. Role of non-surgical/ non-endoscopic approach (only ERCP) in Jaundiced patients 22. Transhepatic drainage should be proposed for compromised patients with severe cholecystitis, refractory to medical treatment at 24 h in COVID-19 positive patients 78% 23. In COVID-19 positive patients with common bile duct and gall bladder stones a sequential approach (ERCP followed by Laparoscopy) should be preferred to a Laparo-Endoscopic Rendez-Vous (LERV) approach to reduce the risk of a pro-Patients with obstructive common bile duct stones should be treated according to the severity of cholangitis regardless of the COVID-19 status, favouring medical treatment 77% 25. Patients with a non-calcular obstructive jaundice should be referred to tertiary centres in order to choose the best treatment (PTBD-ERCP-upfront surgery) 84% 26. Upfront surgery should not be offered to COVID-19 positive patients with non-calcular obstructive jaundice 80% 27. Cholecystectomy should be indicated in severe cholecystitis that is not responsive to conservative or interventional treatment, even COVID-19 positive patients 89% Abdominal wall hernias 8. What are specific measures in abdominal wall hernia surgery that should be considered during COVID-19 pandemic regarding? 28. Laparoscopic approach to incarcerated ventral and inguinal hernia may be safe in COVID-19 positive patients if laparoscopy is not otherwise contraindicated 80% a. Laparoscopy in incarcerated ventral/incisional hernia b. Laparoscopy in incarcerated inguinal hernia c. Role of meshes in emergency 29. In COVID-19 unknown patients, delaying surgery of an incarcerated ventral and inguinal hernia to obtain test results may not be justified 89% d. Role of techniques that might increase intraabdominal pressure 30. The use of mesh for hernia repair may not increase the risk of complications in COVID-19 positive patients 89% e. Surgical approach if a bowel resection is needed 31. Laparoscopic approach to incarcerated hernia requiring bowel resection may be safe for COVID-19 positive patients if not otherwise contraindicated What is the role for flexible endoscopy mitigating the risk of surgery during COVID-19 pandemic in the following situations? 32. Flexible endoscopic therapy should be the first attempt to treat upper GI bleeding even in patients affected by COVID-19 COVID-19 positive patients with an obstructing esophageal or gastric cancer should be treated first by endoscopic stenting if possible, in order to delay surgery until conditions are more favourable to operate 81% 10. What is the role for surgical endoscopy during COVID-19 pandemic in the following situations? 34. COVID-19 positive patients with an immediate presentation of benign esophageal perforation (of less than 24 h) should be treated first by flexible endoscopy means, while those perforated present after 24 h should undergo immediate surgery [/table]

Caco-2 Caco-2 refers to a cell monolayer absorption model. Cell-based functional assays, such as the Caco-2 drug transport model for assessing intestinal transport, are extremely valuable for screening lead compounds in drug discovery. The Caco-2 cell line was developed by the Sloan-Kettering Institute for Cancer Research through research conducted by Dr. Jorgen Fogh. The Caco-2 cell line is widely used with in vitro assays to predict the absorption rate of candidate drug compounds across the intestinal epithelial cell barrier. The assay requires that drug absorption rates be determined 21 days after Caco-2 cell seeding to allow for monolayer formation and cell differentiation. The Caco-2 cell line is a continuous line of heterogeneous human epithelial colorectal adenocarcinoma cells, developed by the Sloan-Kettering Institute for Cancer Research through research conducted by Dr. Jorgen Fogh. Although derived from a colon (large intestine) carcinoma, when cultured under specific conditions the cells become differentiated and polarized such that their phenotype, morphologically and functionally, resembles the enterocytes lining the small intestine. Caco-2 cells express tight junctions, microvilli, and a number of enzymes and transporters that are characteristic of such enterocytes: peptidases, esterases, P-glycoprotein, uptake transporters for amino acids, bile acids carboxylic acids, etc. They are commercially available through the American Type Culture Collection (ATCC; Manassas, VA, USA). When looking at Caco-2 cell cultures microscopically, it is evident even by visual inspection that the cells are heterogeneous. As a result, over the years the characteristics of the cells used in different laboratories around the world have diverged significantly, which makes it difficult to compare results across labs. Caco-2 cells are most commonly used not as individual cells, but as a confluent monolayer on a cell culture insert filter (e.g., Transwell®). When cultured in this format, the cells differentiate to form a polarized epithelial cell monolayer that provides a physical and biochemical barrier to the passage of ions and small molecules . The Caco-2 monolayer is widely used across the pharmaceutical industry as an in vitro model of the human small intestinal mucosa to predict the absorption of orally administered drugs. The correlation between the in vitro apparent permeability (P¬app) across Caco-2 monolayers and the in vivo fraction absorbed (fa) is well established.Transwell diagram This application of Caco-2 cells was pioneered in the late 1980s by Ismael Hidalgo, working in the laboratory of Ron Borchardt at the University of Kansas, and Tom Raub, who was at the Upjohn Company at the time. Following stints at SmithKline Beecham and Rhone-Poulenc Rorer, Hidalgo went on to co-found a company, Absorption Systems, in 1996, where he remains as Chief Scientist. The considerable impact of the Caco-2 cell monolayer model can be measured in at least two ways. First, considering that poor pharmacokinetic properties accounted for ~40% of drug failures in development in the early 1990s and only ~10% by 2009, an interval in which Caco-2 monolayers were widely used throughout the pharmaceutical industry to predict absorption, it is not unreasonable to attribute some of that shift to this simple yet powerful model. Second, the 1989 Gastroenterology paper that demonstrated the utility of the model for this application has been cited more than 1000 times since its publication. The versatility of Caco-2 cells is demonstrated by the fact that, even to this day, they are serving as the basis for the creation of innovative new models that are contributing to our understanding of drug efflux transporters such as P-glycoprotein (ABCB1) and BCRP (ABCG2). RNA interference has been used to silence the expression of individual efflux transporters, either transiently or long-term.

Parecoxib # Overview Parecoxib is a water soluble and injectable prodrug of valdecoxib. It is marketed as Dynastat in the European Union. Parecoxib is a COX2 selective inhibitor in the same category as celecoxib (Celebrex) and rofecoxib (Vioxx). As it is injectable, it can be used perioperatively when patients are unable to take oral medications. It is approved through much of Europe for short term perioperative pain control much in the same way ketorolac (Toradol) is used in the United States. However, unlike ketorolac, parecoxib has no effect on platelet function and therefore does not promote bleeding during or after surgery. In addition, ketorolac has a much higher gastrointestinal toxicity profile compared to most other nonsteroidal antiinflammatory drugs (NSAIDs) including ibuprofen and naprosyn. However, in the United States ketorolac is the only injectable NSAID, although it is banned in many European countries due to concerns about surgical bleeding and stomach ulcers after surgery. In 2005, the U.S. Food and Drug Administration (FDA) issued a letter of non-approval for parecoxib in the United States. No reasons were ever documented publicly for the non-approval, although one study noted increased occurrences of heart attacks following cardiac bypass surgery compared to placebo when high doses of parecoxib were used to control pain after surgery. It is also important to remember that rare but severe allergic reactions (Stevens-Johnson Syndrome, Lyell Syndrome) have been described with valdecoxib, the molecule to which parecoxib is converted. The drug is not approved for use after cardiac surgery in Europe. Ketorolac, still banned in much of Europe, and IV Ibuprofen are therefore the only options for IV NSAIDs in the United States, and it is not clear whether parecoxib will be resubmitted to the FDA in the future. All anti-inflammatory medications in the U.S. carry the same warning regarding skin reactions, and none are approved for use during CABG surgery, so the reason for the FDA denying the approval of parecoxib remains unknown, but was likely related to political pressure from the US Congress to not approve another COX-2 selective inhibitor in the wake of the Vioxx affair. No COX-2 selective inhibitor has been approved in the US since that time, regardless of the safety profile of parecoxib in Europe. Efforts to find out the scientific rationale, or more likely the lack thereof, that the FDA used to justify the non-approval of parecoxib in the USA have proven futile due to secrecy issues.

Niacin/Simvastatin contraindications # Contraindications SIMCOR is contraindicated in the following conditions: - Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels - Patients with active peptic ulcer disease - Patients with arterial bleeding - Concomitant administration of strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin,clarithromycin, telithromycin and nefazodone) - Concomitant administration of gemfibrozil, cyclosporine, or danazol - Concomitant administration of verapamil or diltiazem - Women who are pregnant or may become pregnant. SIMCOR may cause fetal harm when administered to a pregnant woman. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of SIMCOR use during pregnancy; however in rare reports congenital anomalies were observed following intrauterine exposure to HMG-CoA reductase inhibitors. If SIMCOR is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus . In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. There are no animal reproductive studies conducted with niacin. - Nursing mothers. SIMCOR contains simvastatin and nicotinic acid. Nicotinic acid is excreted into human milk and it is not known whether simvastatin is excreted into human milk; however a small amount of another drug in this class does pass into breast milk. Because of the potential for serious adverse reactions in nursing infants, women who require SIMCOR treatment should not breastfeed their infants . - Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including one of more of the following adverse reactions have been reported for simvastatin and/or niacin extended-release: anaphylaxis, angioedema, urticaria, fever, dyspnea, tongue edema, larynx edema, face edema, peripheral edema, laryngismus, and flushing .

Pneumonia (community-acquired): antimicrobial prescribing This guideline sets out an antimicrobial prescribing strategy for community-acquired pneumonia. It aims to optimise antibiotic use and reduce antibiotic resistance. # Recommendations # Managing community-acquired pneumonia ## Treatment for adults, young people and children Offer an antibiotic(s) for adults, young people and children with community-acquired pneumonia. When choosing an antibiotic (see the recommendations on choice of antibiotic), take account of: the severity assessment for adults, as set out in table 1 the severity of symptoms or signs for children and young people, based on clinical judgement the risk of developing complications, for example, if the person has relevant comorbidity such as severe lung disease or immunosuppression local antimicrobial resistance and surveillance data (such as flu and Mycoplasma pneumoniae infection rates) recent antibiotic use recent microbiological results, including colonisation with multidrug-resistant bacteria.At the time of publication (September 2019), no validated severity assessment tools are available for children and young people with community-acquired pneumonia, and severity of symptoms or signs should be based on clinical judgement. Start antibiotic treatment as soon as possible after establishing a diagnosis of community-acquired pneumonia, and certainly within 4 hours (within 1 hour if the person has suspected sepsis and meets any of the high risk criteria for this – see the NICE guideline on sepsis). Give oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics. If intravenous antibiotics are given, review by 48 hours and consider switching to oral antibiotics if possible. This recommendation has been removed. For children and young people in hospital with community-acquired pneumonia, and severe symptoms or signs or a comorbidity, consider sending a sample (for example, sputum sample) for microbiological testing. ## Advice Give advice to adults, young people and children with community-acquired pneumonia about: possible adverse effects of the antibiotic(s) how long symptoms are likely to last seeking medical help (if the person is receiving treatment in the community) if: symptoms worsen rapidly or significantly or symptoms do not start to improve within 3 days or the person becomes systemically very unwell. ## Reassessment Reassess adults, young people and children with community-acquired pneumonia if symptoms or signs do not improve as expected or worsen rapidly or significantly. When reassessing adults, young people and children with community-acquired pneumonia, be aware of possible non-bacterial causes, such as flu. If a sample has been sent for microbiological testing: review the choice of antibiotic(s) when results are available and consider changing the antibiotic(s) according to results, using a narrower-spectrum antibiotic, if appropriate. Send a sample (for example, a sputum sample) for microbiological testing if symptoms or signs have not improved following antibiotic treatment, and this has not been done already. ## Referral and seeking specialist advice Refer adults with community-acquired pneumonia to hospital if they have: any symptoms or signs suggesting a more serious illness or condition (for example, cardiorespiratory failure or sepsis) or symptoms that are not improving as expected with antibiotics. Consider referring adults with community-acquired pneumonia to hospital, or seek specialist advice, if they: have bacteria that are resistant to oral antibiotics or cannot take oral medicines (exploring locally available options for giving intravenous antibiotics at home or in the community, rather than in hospital, if this is appropriate). Consider referring children and young people with community-acquired pneumonia to hospital, or seek specialist paediatric advice on further investigation and management. See the evidence and committee discussion on antibiotic prescribing strategies and choice of antibiotics. # Choice of antibiotic When prescribing an antibiotic(s) for community-acquired pneumonia: follow table 1 for adults aged 18 years and over follow table 2 for children and young people under 18 years. Treatment Antibiotic, dosage and course length First-choice oral antibiotic if low severity (based on clinical judgement and guided by a CRB65 score 0 or a CURB65 score 0 or 1 when these scores can be calculated) Amoxicillin: mg three times a day (higher doses can be used; see the BNF) for 5 days Alternative oral antibiotics if low severity, for penicillin allergy or if amoxicillin unsuitable (for example, if atypical pathogens suspected) Doxycycline: mg on first day, then 100 mg once a day for 4 days (5‑day course in total) Clarithromycin: mg twice a day for 5 days Erythromycin (in pregnancy): mg four times a day for 5 days First-choice oral antibiotics if moderate severity (based on clinical judgement and guided by a CRB65 score 1 or 2, or a CURB65 score 2 when these scores can be calculated; guided by microbiological results when available) Amoxicillin: mg three times a day (higher doses can be used; see the BNF) for 5 days With (if atypical pathogens suspected) Clarithromycin: mg twice a day for 5 days Or Erythromycin (in pregnancy): mg four times a day for 5 days Alternative oral antibiotics if moderate severity, for penicillin allergy (guided by microbiological results when available) Doxycycline: mg on first day, then 100 mg once a day for 4 days (5‑day course in total) Clarithromycin: mg twice a day for 5 days First-choice antibiotics if high severity (based on clinical judgement and guided by a CRB65 score 3 or 4, or a CURB65 score 3 to 5 when these scores can be calculated; guided by microbiological results when available) Co‑amoxiclav: /125 mg three times a day orally or 1.2 g three times a day intravenously for 5 days With Clarithromycin: mg twice a day orally or intravenously for 5 days Or Erythromycin (in pregnancy): mg four times a day orally for 5 days Alternative antibiotic if high severity, for penicillin allergy (guided by microbiological results when available; consult a local microbiologist if fluoroquinolone not appropriate) Levofloxacin (consider safety issues): mg twice a day orally or intravenously for 5 days See the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding, and administering intravenous (or, where appropriate, intramuscular) antibiotics. Give oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics. Review intravenous antibiotics by 48 hours and consider switching to oral antibiotics if possible. Stop antibiotic treatment after 5 days unless microbiological results suggest a longer course is needed or the person is not clinically stable, for example, if they have had a fever in the past 48 hours or have more than 1 sign of clinical instability (systolic blood pressure less than 90 mmHg, heart rate more than 100/minute, respiratory rate more than 24/minute, arterial oxygen saturation less than 90% or partial pressure of oxygen of more than 60 mmHg in room air). For fluoroquinolone antibiotics, see Medicines and Healthcare products Regulatory Agency (MHRA) advice for restrictions and precautions because of very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution for people over 60 years and avoiding coadministration with a corticosteroid (March 2019). Consider adding a macrolide to amoxicillin if atypical pathogens are suspected, and review when microbiological results are available. Mycoplasma pneumoniae infection occurs in outbreaks approximately every 4 years. Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy. CRB65: confusion, respiratory rate 30/minute or more, blood pressure (systolic less than 90 mmHg or diastolic 60 mmHg or less), age 65 or more CURB65: confusion, urea more than 7 mmol/litre, respiratory rate 30/minute or more, blood pressure (systolic less than 90 mmHg or diastolic 60 mmHg or less), age 65 or more Treatment Antibiotic, dosage and course length Children under 1 month Refer to paediatric specialist First-choice oral antibiotic for children 1 month and over if non-severe symptoms or signs (based on clinical judgement) Amoxicillin: month to 11 months, 125 mg three times a day for 5 days year to 4 years, 250 mg three times a day for 5 days years to 17 years, 500 mg three times a day for 5 days (higher doses can be used for all ages; see BNF for children) Alternative oral antibiotics if non-severe symptoms or signs (based on clinical judgement), for penicillin allergy or if amoxicillin unsuitable (for example, atypical pathogens suspected) Clarithromycin: month to 11 years: Under 8 kg, 7.5 mg/kg twice a day for 5 days kg to 11 kg, 62.5 mg twice a day for 5 days kg to 19 kg, 125 mg twice a day for 5 days kg to 29 kg, 187.5 mg twice a day for 5 days kg to 40 kg, 250 mg twice a day for 5 days years to 17 years: mg to 500 mg twice a day for 5 days Erythromycin (in pregnancy): years to 17 years, 250 mg to 500 mg four times a day for 5 days Doxycycline: years to 17 years, 200 mg on first day, then 100 mg once a day for 4 days (5‑day course in total) (see BNF for children for use of doxycycline in children under 12) First-choice antibiotic(s) if severe symptoms or signs (based on clinical judgement; guided by microbiological results when available) Co‑amoxiclav: Oral doses: month to 11 months, 0.5 ml/kg of 125/31 suspension three times a day for 5 days years to 5 years, 10 ml of 125/31 suspension three times a day or 0.5 ml/kg of 125/31 suspension three times a day for 5 days (or 5 ml of 250/62 suspension) years to 11 years, 10 ml of 250/62 suspension three times a day or 0.3 ml/kg of 250/62 suspension three times a day for 5 days years to 17 years, 500/125 mg three times a day for 5 days Intravenous doses: month to 2 months, 30 mg/kg twice a day months to 17 years, 30 mg/kg three times a day (maximum 1.2 g per dose three times a day) With (if atypical pathogen suspected) Clarithromycin: Oral doses: month to 11 years: Under 8 kg, 7.5 mg/kg twice a day for 5 days kg to 11 kg, 62.5 mg twice a day for 5 days kg to 19 kg, 125 mg twice a day for 5 days kg to 29 kg, 187.5 mg twice a day for 5 days kg to 40 kg, 250 mg twice a day for 5 days years to 17 years: mg to 500 mg twice a day for 5 days Intravenous doses: month to 11 years, 7.5 mg/kg twice a day (maximum 500 mg per dose) years to 17 years, 500 mg twice a day Or Erythromycin (in pregnancy): years to 17 years, 250 mg to 500 mg four times a day orally for 5 days Alternative antibiotics if severe symptoms or signs(based on clinical judgement), for penicillin allergy (guided by microbiological results when available) Consult local microbiologist See the BNF for children for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding, and administering intravenous (or, where appropriate, intramuscular) antibiotics. The age bands apply to children of average size and, in practice, the prescriber will use the age bands in conjunction with other factors such as the severity of the condition being treated and the child's size in relation to the average size of children of the same age. Give oral antibiotics first line if the person can take oral medicines, and the severity of their condition does not require intravenous antibiotics. Review intravenous antibiotics by 48 hours and consider switching to oral antibiotics if possible. Stop antibiotic treatment after 5 days unless microbiological results suggest a longer course is needed or the person is not clinically stable (fever in past 48 hours or more than 1 sign of clinical instability ). Mycoplasma pneumoniae infection occurs in outbreaks approximately every 4 years and is more common in school-aged children. Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy. See the committee discussions on choice of antibiotics and antibiotic course length. # Terms used in the guideline ## Severe community-acquired pneumonia in children and young people Features of severe community-acquired pneumonia in children and young people include difficulty breathing, oxygen saturation less than 90%, raised heart rate, grunting, very severe chest indrawing, inability to breastfeed or drink, lethargy and a reduced level of consciousness. ## CRB65 CRB65 is used in primary care to assess 30‑day mortality risk in adults with pneumonia. The score is calculated by giving 1 point for each of the following prognostic features: confusion, respiratory rate 30/minute or more, low systolic or diastolic blood pressure, age 65 or more). Risk of death is stratified as follows: : low risk (less than 1% mortality risk) -r 2: intermediate risk (1% to 10% mortality risk) -r 4: high risk (more than 10% mortality risk). ## CURB65 CURB65 is used in hospital to assess 30‑day mortality risk in adults with pneumonia. The score is calculated by giving 1 point for each of the following prognostic features: (confusion, urea more than 7 mmol/litre, respiratory rate 30/minute or more, low systolic or diastolic blood pressure, age 65 or more). Risk of death is stratified as follows: -r 1: low risk (less than 3% mortality risk) : intermediate risk (3% to 15% mortality risk) to 5: high risk (more than 15% mortality risk). Adults with score of 1 and particularly 2 are at increased risk of death (should be considered for hospital referral) and people with a score of 3 or more are at high risk of death (require urgent hospital admission).# Summary of the evidence This is a summary of the evidence. For full details, see the evidence review. Community‑acquired pneumonia is a lower respiratory tract infection that is most commonly caused by bacterial infection (British Thoracic Society guideline on community-acquired pneumonia in adults, 2009). The main bacterial pathogen is Streptococcus pneumoniae (NICE clinical knowledge summaries on chest infections in adults, 2015), however Mycoplasma pneumoniae occurs in outbreaks approximately every 4 years in the UK and is much more common in school-aged children (BTS 2009). Although bacterial infection is the most common cause of community-acquired pneumonia, viral infection causes approximately 13% of cases in adults (BTS 2009) and approximately 66% of cases in children and young people (Jain et al. 2015). Low-severity, community-acquired pneumonia in adults includes people with pneumonia severity index (PSI) score of I or II, CRB65 score 0 or CURB65 score 0 or 1. Moderate- to high-severity, community-acquired pneumonia in adults includes people with PSI score of III to V, CRB65 score 1 to 4 or CURB65 score 2 to 5. The severity of infection was not always clearly defined in the studies, and was often based on clinical judgement. The management setting (community or hospital) was used to indicate the severity of symptoms when this was not described in the studies (through either severity assessment scores or clinical judgement). # Antibiotic prescribing strategies In adults with moderate‑ to high-severity community-acquired pneumonia, an antibiotic prescribing strategy guided by results of pneumococcal and Legionella pneumophila urine antigen tests was not significantly different from a strategy that used broad-spectrum antibiotics without antigen testing for the outcomes of mortality, clinical relapse and hospital admissions (1 randomised controlled trial , Falguera et al. 2009). In adults with mixed severity community-acquired pneumonia, a strategy of stopping antibiotics based on guidelines was not different to physician-guided stopping for a range of outcomes, including mortality, symptoms, recurrence, length of hospital stay and adverse events. Stopping antibiotics based on guidelines was associated with a longer total antibiotic course length (including intravenous and oral antibiotics) but with a shorter time taking intravenous antibiotics (2 RCTs, Uranga et al. 2016 and Aliberti et al. 2017). In children aged 1 month to 5 years with severe community-acquired pneumonia, a strategy of intravenous antibiotics then switching to oral antibiotics (based on a specified drop in body temperature and stable clinical signs) reduced hospital stay by about 1 day, compared with standard care (intravenous then switching to oral antibiotics at least 48 hours after dissipation of fever). There was no difference in readmissions (1 non-inferiority RCT, In-iw et al. 2015). Committee discussions on antibiotic prescribing strategies The committee discussed that the study designs were not appropriate for determining which antibiotic prescribing strategies were most effective, because the antibiotics used in the studies on prescribing strategies had very broad antibacterial cover. The committee discussed that although community-acquired pneumonia can be caused by a viral infection, it is difficult to distinguish this from a bacterial infection. Based on the high mortality rate, the committee agreed that all people with community-acquired pneumonia should be offered an antibiotic. The committee was aware that the NICE guideline on pneumonia in adults (2014) recommended antibiotic treatment as soon as possible, and within 4 hours for people admitted to hospital with community-acquired pneumonia. The committee agreed that this was also applicable to people receiving treatment in the community. The committee also agreed that people with suspected sepsis and high risk criteria (as described in the NICE guideline on sepsis) would need more urgent treatment. Because there were no major differences between stopping antibiotics based on guidelines and stopping antibiotics based on clinical judgement, the committee agreed that clinical judgement should be used when deciding when to stop antibiotic treatment. This should usually be after 5 days. The committee agreed that the criteria (fever in the past 48 hours, blood pressure, heart rate, respiratory rate and oxygen saturations) used in the study by Uranga et al. (2016) should be considered during decision making (see the committee discussion on antibiotic course length). The committee discussed the evidence in children suggesting a reduced length of hospital stay with switching from intravenous to oral antibiotics when clinical signs were stable compared with switching following 48 hours of dissipation of fever. However, because other important clinical outcomes were not reported (such as mortality or cure), and no evidence was available in adults for this prescribing strategy, the committee agreed that if applicable, the decision for switching from intravenous to oral antibiotics in adults, young people and children should be based on clinical judgement (see the evidence summary and committee discussion section on route of administration). In children and young people with severe symptoms or signs, the committee agreed that a broad-spectrum antibiotic would be needed initially to cover the range of possible pathogens, including the addition of a macrolide if atypical pneumonia was suspected (see the committee discussion on choice of antibiotics). The committee was concerned about the risk of antimicrobial resistance from using broad-spectrum antibiotics for longer than necessary. Therefore, the committee agreed that in children and young people in hospital, with severe symptoms or signs or a comorbidity (who were more likely to be on broad-spectrum antibiotics), sending a sample for microbiological testing should be considered. They recognised that obtaining a sample for testing is not always possible, especially in young children. The committee agreed that when microbiological results are available, the antibiotic should be reviewed and changed accordingly (for example, if bacteria are found to be resistant or atypical pathogens are not isolated) if symptoms are not already improving, using a narrower-spectrum antibiotic if appropriate. The committee agreed that first-line antibiotics would be effective in most children and young people with non‑severe symptoms or signs, and therefore microbiological testing would not be needed routinely to guide antibiotic choice. # Choice of antibiotics ## Efficacy of antibiotics Low-severity community-acquired pneumonia in adults There were no differences in the clinical effectiveness of the following antibiotic comparisons (course length varied but usually ranged from 7 to 14 days) in adults with low-severity community-acquired pneumonia: clarithromycin compared with amoxicillin (Pakhale et al. 2014) clarithromycin compared with erythromycin (Pakhale et al. 2014) azithromycin compared with clarithromycin (Pakhale et al. 2014) azithromycin compared with co‑amoxiclav (Paris et al. 2008) azithromycin compared with levofloxacin (Pakhale et al. 2014) a cephalosporin (cefuroxime or cefditoren) compared with co‑amoxiclav (Maimon et al. 2008) levofloxacin compared with ceftriaxone plus azithromycin (Raz-Pasteur et al. 2015). Some differences were seen for some efficacy outcomes for other antibiotic comparisons in adults with low-severity community-acquired pneumonia. Amoxicillin improved clinical cure rates (in intention-to-treat analysis only) and complete resolution at 30 days, compared with phenoxymethylpenicillin (Llor et al. 2017). Cefixime significantly reduced respiratory rate, radiological consolidations and bacterial isolates compared with ciprofloxacin, but there was no significant differences in temperature reduction or pulse rate (Ige et al. 2015). Evidence for efficacy of antibiotics for low-severity community-acquired pneumonia in adults is based on 3 systematic reviews (Pakhale et al. 2014, Maimon et al. 2008 and Raz-Pasteur et al. 2015), 1 RCT (Ige et al. 2015) and 2 non‑inferiority RCTs (Llor et al. 2017 and Paris et al. 2008). Moderate- to high-severity community-acquired pneumonia in adults There were no differences in the clinical effectiveness of the following antibiotic comparisons (course length varied but usually ranged from 7 to 14 days) in adults with moderate‑ to high-severity community-acquired pneumonia: a macrolide compared with antibiotics targeted at non-atypical pathogens (penicillins, beta-lactam plus beta-lactamase inhibitors, cephalosporins and carbapenems; Eliakim-Raz et al. 2012) a fluoroquinolone compared with antibiotics targeted at non-atypical pathogens (penicillins, beta-lactam plus beta-lactamase inhibitors and cephalosporins; Eliakim-Raz et al. 2012) levofloxacin compared with tigecycline (Nemeth et al. 2015) levofloxacin compared with doxycycline (Nemeth et al. 2015) -floxacin compared with erythromycin (Skalsky et al. 2013) moxifloxacin compared with levofloxacin (Yuan et al. 2012) ertapenem compared with ceftriaxone (Bai et al. 2014) a macrolide compared with a beta-lactam antibiotic plus macrolide (Raz-Pasteur et al. 2015) a fluoroquinolone compared with a beta-lactam antibiotic plus fluoroquinolone (Raz-Pasteur et al. 2015) ceftriaxone plus azithromycin compared with ceftriaxone plus a macrolide (clarithromycin or erythromycin; Tamm et al. 2007) ceftobiprole compared with ceftriaxone plus linezolid (in suspected methicillin-resistant Staphylococcus aureus infection (Nicholson et al. 2012). For other antibiotic comparisons in adults with moderate‑ or high-severity community-acquired pneumonia, some differences were seen in some efficacy outcomes: Antibiotics targeted at atypical pathogens (macrolides and fluoroquinolones) compared with antibiotics targeted at non-atypical pathogens (penicillins, beta‑lactam plus beta-lactamase inhibitors, cephalosporins and carbapenems): overall there were no significant differences in mortality or clinical failure, but there was significantly less bacteriological failure with antibiotics targeted at atypical pathogens. Some minor differences were seen in subgroup analyses, including significantly lower clinical failure with antibiotics targeted at atypical pathogens in adults with Legionella pneumophila infection (Eliakim-Raz et al. 2012). Ceftriaxone compared with ceftaroline fosamil: there was no significant difference in mortality, but clinical cure was significantly increased with ceftriaxone (El Hajj et al. 2017). A fluoroquinolone (levofloxacin or moxifloxacin) compared with a beta-lactam antibiotic plus macrolide: there were no significant differences in mortality or microbiological failure, but clinical failure was significantly reduced with a fluoroquinolone (result not significant in adults with pneumococcal pneumonia; Raz-Pasteur et al. 2015). A beta-lactam antibiotic (co‑amoxiclav or cefuroxime) plus upfront clarithromycin (upfront dual therapy) compared with a beta-lactam antibiotic (co‑amoxiclav or cefuroxime) plus clarithromycin only when a positive Legionella pneumophila urine sample was confirmed (test-dependant dual therapy): there was no significant difference in mortality or clinical stability; in people with an atypical (but not non-atypical) infection, upfront dual therapy was significantly better for achieving clinical stability compared with test-dependant dual therapy; there were no significant differences in admission to intensive care, incidence of complicated pleural effusion, length of hospital stay or long-term readmission rates. Evidence for efficacy of antibiotics for moderate-to high‑severity community-acquired pneumonia in adults is based on 7 systematic reviews (Eliakim-Raz et al. 2012, Nemeth et al. 2015, Skalsky et al. 2013, El Hajj et al. 2017, Yuan et al. 2012, Bai et al. 2014 and Raz-Pasteur et al. 2015) and 3 non-inferiority RCTs (Garin et al. 2014, Nicholson et al. 2012 and Tamm et al. 2007). Non-severe community-acquired pneumonia in children and young people Evidence (1 systematic review, Lodha et al. 2013) was identified on the following antibiotic comparisons (course length varied but usually ranged from 4 to 10 days) for treatment of non-severe community-acquired pneumonia, for which no significant differences were found for the efficacy outcomes reported: azithromycin compared with erythromycin azithromycin compared with co‑amoxiclav clarithromycin compared with erythromycin co-trimoxazole compared with amoxicillin cefpodoxime compared with co‑amoxiclav For other antibiotic comparisons in children and young people with non-severe community-acquired pneumonia, some differences were seen in the following efficacy outcomes: Co-amoxiclav was significantly better than amoxicillin for improving cure rate (94% versus 60%) and improving poor or no response rate (2% versus 20%) in children aged 2 to 12 years. Amoxicillin was significantly better than chloramphenicol for improving cure rate in children aged 2 to 59 months. Severe community-acquired pneumonia in children and young people Evidence (Lodha et al. 2013 unless otherwise stated) was identified on the following antibiotic comparisons for treatment (course length varied but usually ranged from 3 to 10 days) of severe or very severe community-acquired pneumonia in children and young people, for which no significant differences were found for the outcomes reported: amoxicillin compared with an unspecified penicillin amoxicillin compared with ampicillin amoxicillin compared with cefuroxime amoxicillin compared with clarithromycin levofloxacin compared with beta‑lactam antibiotics (co‑amoxiclav or ceftriaxone) cefuroxime compared with clarithromycin co-trimoxazole compared with chloramphenicol ceftaroline fosamil compared with ceftriaxone (Cannavino et al. 2016). benzylpenicillin plus gentamicin compared with co‑amoxiclav an unspecified penicillin plus chloramphenicol compared with ampicillin benzylpenicillin plus chloramphenicol compared with chloramphenicol an unspecified penicillin plus gentamicin compared with chloramphenicol chloramphenicol plus an unspecified penicillin compared with ceftriaxone ceftriaxone plus vancomycin compared with ceftaroline fosamil (Blumer et al. 2016). For other antibiotic comparisons in children and young people with severe community-acquired pneumonia, some differences were seen in the following efficacy outcomes: Ampicillin plus gentamicin was significantly better than chloramphenicol in children with very severe pneumonia, aged 2 to 59 months for clinical failure at all time points, but there was no significant difference in mortality. Significantly fewer children given ampicillin plus gentamicin needed to change antibiotics before day 21. A penicillin (unspecified) plus gentamicin was not significantly different to chloramphenicol for mortality in children with severe community-acquired pneumonia, aged 1 to 59 months, but readmissions were significantly lower with a penicillin plus gentamicin. Evidence for efficacy of antibiotics for severe community-acquired pneumonia in children and young people is based on 1 systematic review (Lodha et al. 2013) and 2 RCTs (Cannavino et al. 2016 and Blumer et al. 2016). ## Safety of antibiotics Antibiotic-associated diarrhoea is estimated to occur in 2% to 25% of people taking antibiotics, depending on the antibiotic used (NICE CKS on diarrhoea – antibiotic associated). About 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information. People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF, August 2019). Macrolides should be used with caution in people with a predisposition to QT interval prolongation (BNF, August 2019). Tetracyclines, including doxycycline, can deposit in growing bone and teeth (by binding to calcium) causing staining and occasionally dental hypoplasia. They should not be given to pregnant or breastfeeding women, and use in children under 12 years is either contraindicated or cautioned for use in severe or life-threatening infections where there are no alternatives (BNF, August 2019). Fluoroquinolones have restrictions and precautions around their use because of rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems (MHRA Drug Safety Update, March 2019). They may also be associated with a small increased risk of aortic aneurysm and dissection, particularly in older people (MHRA Drug Safety Update, November 2018). Tendon damage (including rupture) has been reported rarely in people receiving fluoroquinolones (BNF, August 2019). Overall, adverse effects of antibiotics were similar in the studies, although some differences were seen for the following antibiotic comparisons in people with community-acquired pneumonia: Adverse events were significantly higher with azithromycin compared with levofloxacin (19.9% versus 12.3%) and erythromycin compared with clarithromycin (45.7% versus 21.4%; Pakhale et al. 2014), and abdominal pain was significantly worse with azithromycin compared with co‑amoxiclav (9.6% versus 1.5%; Paris et al. 2008), in adults with low-severity community-acquired pneumonia. Adverse events, treatment discontinuations and diarrhoea were significantly lower with a fluoroquinolone compared with beta-lactam antibiotic plus a macrolide in adults with moderate- to high-severity community-acquired pneumonia (Raz-Pasteur et al. 2015). Adverse events were significantly lower with a macrolide compared with a beta-lactam antibiotic plus macrolide in adults with moderate‑ to high-severity community-acquired pneumonia (Raz-Pasteur et al. 2015). Adverse events were significantly higher with ceftobiprole compared with ceftriaxone plus linezolid in adults with suspected MRSA infection (Nicholson et al. 2012). Adverse events were significantly lower with azithromycin compared with co‑amoxiclav in children with non-severe community-acquired pneumonia (Lodha et al. 2013). Significantly more children with severe community-acquired pneumonia had 1 or more adverse events with ceftriaxone plus vancomycin compared with ceftaroline fosamil (Blumer et al. 2016). See the summaries of product characteristics for information on contraindications, cautions, drug interactions and adverse effects of individual medicines. Committee discussions on choice of antibiotics The committee noted that using the care setting as a proxy for the severity of community-acquired pneumonia may not always be appropriate, and that some studies in outpatients may include people with moderate-severity community-acquired pneumonia, or a mixed severity population. They recognised that hospital admission criteria in other countries may differ from UK practice. The committee discussed the pathogens which cause community-acquired pneumonia and noted that Streptococcus pneumoniae is the most common cause. Based on their experience, the committee noted that atypical pathogens are the causative organism in around 10% to 15% of moderate- to high-severity infections. Adults with community-acquired pneumonia The committee discussed the evidence on choice of antibiotics in adults with low-severity community-acquired pneumonia and in adults with moderate- to high-severity community-acquired pneumonia. The committee was aware that the CRB65 (in primary care) and CURB65 (in hospital) mortality risk scores were recommended in the NICE guideline on pneumonia in adults for assessing the risk of mortality with community-acquired pneumonia. The committee discussed evidence which used the pneumonia severity index to assess severity; however, they agreed that, when they can be calculated, CRB65 and CURB65 scores should be used in conjunction with clinical judgement to assess severity in adults. Based on limited evidence showing no major differences in clinical effectiveness between antibiotics or classes of antibiotics, the committee agreed that the choice of antibiotic should largely be driven by their experience of which antibiotics have good activity against likely pathogens and cause the least harm, with as narrow spectrum as possible to minimise the risk of antimicrobial resistance. The committee considered the adverse effects associated with individual antibiotics, for example, increased risk of Clostridium difficile infection, along with the risk of harm from not adequately treating the infection. Based on their experience, the first-choice antibiotic for adults with low-severity community-acquired pneumonia is amoxicillin (a penicillin), which has good activity against Streptococcus pneumoniae and is associated with fewer adverse effects and relatively low resistance rates. Amoxicillin is routinely used as first-line treatment and the committee agreed that there was no evidence to support changing current practice. Alternative antibiotics are doxycycline (a tetracycline), clarithromycin (a macrolide) and erythromycin (an alternative macrolide in pregnancy), for people with low-severity community-acquired pneumonia and penicillin allergy, or when amoxicillin may not be appropriate, for example, if an atypical infection is suspected. These antibiotics have good activity against Streptococcus pneumoniae; however, because of their broader spectrum of activity (and because some of them also have additional safety warnings), the committee agreed that these antibiotics should be used only when there is a clinical reason not to use amoxicillin. The committee discussed the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides. Although evidence for doxycycline was not identified in people with low-severity community-acquired pneumonia, the committee agreed that evidence identified in hospitalised adults could include a mixed severity population. From its experience, the committee agreed that doxycycline is an appropriate choice as an alternative to a macrolide. The committee discussed the evidence of effectiveness for azithromycin. However, it agreed that because of its long half-life and therefore increased likelihood of resistance, it was a less suitable choice than other macrolides. From its experience, the committee agreed that although the available evidence does not differentiate between people with moderate-severity disease and those with high-severity disease, there is a clinical distinction between these groups which require different treatment options. Therefore, separate recommendations on antibiotic choice were made for moderate-severity and high-severity community-acquired pneumonia. The committee recognised that there was not clear evidence that the addition of a macrolide to amoxicillin was effective for treating moderate- to high-severity community-acquired pneumonia in adults, although this was current routine practice. However, the committee had concerns about the consistency and quality of the evidence identified. Based on their experience, the first-choice antibiotic for adults with moderate-severity community-acquired pneumonia is amoxicillin (a penicillin), with the addition of a macrolide if an atypical pathogen is suspected. Choices of macrolides are clarithromycin or erythromycin (in pregnancy). The committee based this decision on its experience of current practice, and because dual therapy with amoxicillin plus a macrolide provides broader spectrum of activity which is more likely to target atypical pathogens. In this population when the causative pathogen is not known, the risk of adverse effects and increased antimicrobial resistance with dual therapy is likely to be outweighed by the clinical benefit. Based on its experience, the committee agreed that if dual therapy with amoxicillin plus a macrolide is given to people with moderate-severity community-acquired pneumonia, this should be reviewed when microbiological results are available. Microbiological results may be useful to guide a decision to stop the macrolide, helping to reduce the risk of resistance and adverse effects with dual therapy. Alternative antibiotics for adults with moderate-severity community-acquired pneumonia and penicillin allergy are doxycycline (a tetracycline) or clarithromycin (a macrolide) alone. This is based on the committee's experience that these antibiotics have good activity against Streptococcus pneumoniae, as well as atypical infections. The committee noted that there are no reasonable alternatives for dual therapy in adults who are unable to take a penicillin, for example, due to penicillin allergy. The committee discussed evidence that fluoroquinolone monotherapy (levofloxacin or moxifloxacin) was as effective as beta-lactam plus macrolide dual therapy for people with moderate- to high-severity community-acquired pneumonia. However, they noted the safety concerns with fluoroquinolones, such as tendon damage and aortic aneurysm. The committee noted that the licence is restricted in community-acquired pneumonia, and agreed that fluroquinolones should only be used when other medicines cannot be prescribed or have been ineffective. The committee agreed that if first and alternative antibiotic choices are not appropriate for adults with low- or moderate-severity community-acquired pneumonia, clinical judgement or seeking specialist advise from a local microbiologist is appropriate. Based on its experience, the first-choice antibiotic for adults with high-severity community-acquired pneumonia is co‑amoxiclav (a penicillin with a beta-lactamase inhibitor) with clarithromycin or erythromycin (in pregnancy). This provides broad-spectrum gram-negative cover and cover for atypical pathogens. The high risk of mortality in this population outweighs the potential adverse effects and increased risk of antimicrobial resistance with broad-spectrum antibiotics. The alternative antibiotic for adults with high-severity community-acquired pneumonia and penicillin allergy is levofloxacin. The committee discussed the evidence of effectiveness for levofloxacin and recognised that Legionella pneumophila infection is more common in this population. The committee agreed that the high risk of mortality without appropriate treatment in this population outweighs the safety concerns and therefore agreed that levofloxacin monotherapy is an appropriate alternative. The committee discussed the evidence that doxycycline is as effective as levofloxacin for adults with moderate- to high-severity community-acquired pneumonia. However, the evidence for doxycycline comes from 1 small study with a 0% mortality rate, suggesting this is not a high-severity population. Therefore, the committee agreed that there is insufficient evidence to recommend doxycycline for this population. The committee agreed that people with high-severity community-acquired pneumonia and penicillin allergy, in whom a fluoroquinolone is not appropriate, is likely to be a small population and specialist microbiological advice should be sought. Children and young people with community-acquired pneumonia The committee was not aware of any validated severity assessment tools for children and young people with community-acquired pneumonia. The committee agreed that features which suggest severe community-acquired pneumonia in children and young people include difficulty breathing, oxygen saturation less than 90%, raised heart rate, grunting, very severe chest indrawing, inability to breastfeed or drink, lethargy and reduced level of consciousness. The severity of symptoms and signs should be assessed by clinical judgement, taking into account these features. Based on the evidence identified and its experience, the committee agreed that it was appropriate to make separate recommendations for non-severe and severe community-acquired pneumonia. Given the specialist expertise needed for treatment of children under 1 month with community-acquired pneumonia, the committee agreed that these children should have their treatment managed by a paediatric specialist. Overall, the committee agreed there was limited evidence relevant to UK practice, and that the evidence had major limitations. Therefore, the committee agreed that the choice of antibiotics in children and young people should largely be driven by its experience of which antibiotics have good activity against likely pathogens and cause the least harm, with as narrow spectrum as possible to minimise the risk of antimicrobial resistance. The committee discussed evidence that co‑amoxiclav was more effective than amoxicillin for children with non-severe community-acquired pneumonia. However, the committee noted that this was based on 1 small RCT within a systematic review, and a lower than expected response rate to amoxicillin was reported compared with other studies in children, which may have been due to sub‑therapeutic dosing. Based on their experience, the first-choice antibiotic for children and young people with community-acquired pneumonia and non-severe symptoms or signs is amoxicillin, which is effective against the most common causative pathogens and is well tolerated. The committee also recognised the clinical experience of the effectiveness of amoxicillin in children and young people, and its common use in current practice. Alternative antibiotics are clarithromycin, erythromycin (in pregnancy) and doxycycline (in young people aged 12 to 17 years only) for children and young people with non-severe symptoms or signs and penicillin allergy, or if amoxicillin is unsuitable (for example, if an atypical pathogen is suspected). These antibiotics have good activity against Streptococcus pneumoniae; however, because of their broader spectrum of activity, the committee agreed that these antibiotics should only be used when there is a clinical reason not to use amoxicillin. The committee agreed that if first and alternative antibiotic choices are not appropriate for children and young people with non-severe community-acquired pneumonia, clinical judgement or seeking specialist advice from a local microbiologist is appropriate. The committee highlighted that the evidence identified for children and young people with severe community-acquired pneumonia was conducted in low-income countries, where severe pneumonia may be more common. The committee was aware that children with severe community-acquired pneumonia in the UK will usually have underlying respiratory conditions. Therefore, the evidence identified may not be directly relevant to UK practice. Based on its experience, the first-choice antibiotic for children and young people with severe community-acquired pneumonia is co‑amoxiclav, with the addition of clarithromycin or erythromycin (in pregnancy) if an atypical pathogen is suspected. The committee discussed that children and young people with severe symptoms or signs are likely to be at higher risk of treatment failure with amoxicillin, and therefore need broader-spectrum antibiotics to target a range of possible causative organisms. Antibiotics to cover atypical pathogens should also be available if atypical infection is suspected. In this population when the causative pathogen is not known, the risk of adverse effects and increased antimicrobial resistance with dual therapy is likely to be outweighed by the clinical benefit. The committee agreed that children and young people with severe community-acquired pneumonia and penicillin allergy is likely to be a small population and specialist microbiological advice should be sought. Safety netting for all people with community-acquired pneumonia The committee recognised that community-acquired pneumonia is potentially a life‑threatening infection and that a person's condition may change rapidly. The committee agreed that advice should be given to adults, young people and children about: the possible adverse effects of the antibiotic and how long symptoms are likely to last and seeking medical help (if the person is receiving treatment in the community) if symptoms worsen rapidly or significantly, do not start to improve within 3 days, or they become systemically very unwell. They agreed that adults, young people and children should be reassessed if symptoms or signs do not improve as expected or worsen rapidly or significantly. If symptoms or signs have not improved following antibiotic treatment, a microbiological sample should be sent for testing if this has not been done already to help guide further treatment. The committee was aware that obtaining a microbiological sample may not always be possible. The committee was aware that community-acquired pneumonia can be caused by a viral infection and therefore agreed that during reassessment, non-bacterial causes of community-acquired pneumonia, such as infection with flu, should be taken into account. The committee was aware of recommendations from NICE guidelines on pneumonia in adults and sepsis that cover when to refer people to hospital. The committee agreed by consensus that adults with any symptoms or signs suggesting a more serious illness or condition or, with symptoms that are not improving as expected with antibiotics, should be referred to hospital if they are being treated in the community. The committee recognised that not all children and young people need to have their treatment managed in hospital, and referral should be based on clinical judgement because no evidence was identified. They agreed that community-acquired pneumonia is less common in children and young people, and that referral to hospital should be considered, or specialist paediatric advice on further investigation and management should be sought. The committee also agreed by consensus that referral or seeking specialist advice should be considered for adults with community-acquired pneumonia who have bacteria that are resistant to oral antibiotics, or who cannot take oral antibiotics (to explore locally available options for giving intravenous antibiotics at home or in the community, rather than in hospital, if this is appropriate). # Antibiotic dosage Low‑dose antibiotics were not significantly different from high‑dose antibiotics for any clinical or bacteriological outcomes reported, in adults with low-severity community-acquired pneumonia: levofloxacin 500 mg once a day compared with levofloxacin 750 mg once a day; 1 non-inferiority RCT, Zhao et al. 2016). co-amoxiclav 875/125 mg three times a day compared with co‑amoxiclav 2000/125 mg twice a day, including in a subgroup analysis of adults with atypical pathogens, S. pneumoniae or H. influenzae infection (1 non-inferiority RCT, Siquier et al. 2006). Low‑dose amoxicillin (45 mg/kg/day divided into 3 doses) was not significantly different to high‑dose amoxicillin (90 mg/kg/day divided into 3 doses) for clinical improvement in young children (2 to 59 months) with non-severe community-acquired pneumonia (1 non-inferiority RCT, Hazir et al. 2007). Amoxicillin given twice a day (total 50 mg/kg/day) was not significantly different to amoxicillin given three times a day at the same dose (total 50 mg/kg/day) for clinical failure rates in young children (2 to 59 months) with non-severe community-acquired pneumonia (1 non-inferiority RCT, Vilas-Boas et al. 2014). Low‑dose benzylpenicillin (200,000 IU/kg/day divided into 4 doses) was not significantly different to high‑dose benzylpenicillin (400,000 IU/kg/day divided into 4 doses) for duration of hospital stay, duration of intravenous treatment or C‑reactive protein levels in young children (3 months to 15 years) with severe community-acquired pneumonia (1 RCT, Amarilyo et al. 2014). No evidence from systematic reviews or RCTs was identified in adults with moderate- or high-severity community-acquired pneumonia. Committee discussions on antibiotic dosage Based on evidence showing no differences between low‑dose and high‑dose antibiotics, and its experience, the committee agreed that usual BNF doses for community-acquired pneumonia (or respiratory tract infections) should be used. However, they recognised the importance of consulting BNF, BNF for children and MHRA advice for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding, and for information on administering intravenous antibiotics. The committee noted that no evidence was identified in adults with moderate- or high-severity community-acquired pneumonia, and only 1 small RCT in young children with severe community-acquired pneumonia was identified. Based on its experience and the higher risk of mortality in people with a severe infection, the committee agreed that where a range of doses are given, the higher dose is appropriate for these people. Based on clinical experience and evidence in adults with low-severity community-acquired pneumonia that high‑dose erythromycin is associated with more adverse effects, the committee agreed that the usual BNF dose for erythromycin should be used when this is recommended as an option for women and young women aged 8 years and over who are pregnant. # Antibiotic course length Short‑course antibiotics (3 to 7 days) were not significantly different to long‑course antibiotics (10 to 14 days) for mortality or clinical failure in adults with low- to moderate-severity community-acquired pneumonia (1 systematic review, Li et al. 2007). Short‑course amoxicillin (3 days) was not significantly different to long‑course amoxicillin (8 days) for clinical cure, bacteriological or radiological success, and length of hospital stay, in adults with low‑ to moderate-severity community-acquired pneumonia (1 RCT, El Moussaoui et al. 2006). Short‑course antibiotics (amoxicillin or co-trimoxazole for 3 days) were not significantly different to a 5‑day course of the same antibiotic for clinical cure or relapse, in young children (2 to 59 months) with non-severe community-acquired pneumonia. The same results were seen when amoxicillin and co‑trimoxazole were analysed separately (1 systematic review, Haider et al. 2008). Short‑course amoxicillin (3 days) was significantly worse than a 10‑day course of amoxicillin (at the same dose) for treatment failure (4/10 versus 0/56) in young children (6 to 59 months) with non-severe community-acquired pneumonia (1 RCT, Greenberg et al. 2014). Short‑course amoxicillin (5 days) was not significantly different to a 10‑day course of amoxicillin (at the same dose) for treatment failure in young children (6 to 59 months) with non-severe community-acquired pneumonia. However, C‑reactive protein at day 5 to 7 was significantly worse with the 5‑day course (1 RCT, Greenberg et al. 2014). No evidence from systematic reviews or RCTs was identified in adults or children with severe community-acquired pneumonia. Committee discussions on antibiotic course length The committee agreed that the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and minimise the risk of adverse effects. However, an effective course length is important in community-acquired pneumonia because this can be a life-threatening infection. The committee discussed evidence for antibiotic course length in adults, young people and children with community-acquired pneumonia. Overall, there did not appear to be major differences between short‑ and long‑course antibiotics, but they noted some inconsistency in the evidence for adults and children. It was also aware that no evidence was identified in children and young people with severe community-acquired pneumonia. The committee agreed that there were several limitations which reduced the applicability of the evidence to UK practice (for example, evidence on antibiotic comparisons not recommended or available in the UK, or a lack of critical outcome reporting). The committee noted the Uranga et al. (2016) study carried out in adults, which found that antibiotics given for a minimum of 5 days, with a strategy of stopping treatment if fever was absent for 48 hours, and there was no more than 1 associated sign of clinical instability, was not different to usual physician's practice. It also noted a similar study (Aliberti et al. 2017), also carried out in adults, which found that antibiotics given for a minimum for 5 days, with a strategy of stopping treatment if clinically stable for 48 hours, was not different to usual physician practice. (See the committee discussion on antibiotic prescribing strategies.) Based on its experience and the risks of antimicrobial resistance with longer courses, the committee agreed by consensus that a 5‑day course of recommended antibiotics was appropriate to treat community-acquired pneumonia for adults, young people and children. # Antibiotic route of administration Intravenous antibiotics switching to oral antibiotics after 2 to 4 days if there was clinical improvement was not significantly different to continuous intravenous antibiotics for mortality, treatment success or recurrence of infection in adults with moderate‑ to high severity community-acquired pneumonia. However, there were significantly fewer days in hospital and adverse events with the switch to oral antibiotics (1 systematic review, Athanassa et al. 2008). Oral antibiotics (amoxicillin or co‑trimoxazole) were not significantly different to intravenous or intermuscular penicillins for clinical failure rate in children and young people (1 month to 18 years) with non-severe community-acquired pneumonia (1 systematic review, Lodha et al. 2013). Oral antibiotics (amoxicillin or co‑trimoxazole) were significantly better than intravenous or intramuscular penicillins for mortality (0.05% versus 0.56%), in children and young people (3 months to 18 years) with severe community-acquired pneumonia. However, there were no significant differences in the rates of cure, clinical failure, hospitalisation or relapse, including when oral amoxicillin was analysed separately (Lodha et al. 2013). Committee discussions on antibiotic route of administration The committee discussed evidence on route of administration, which found that oral antibiotics are as effective as injectable antibiotics for children and young people with non-severe community-acquired pneumonia and are more effective for children and young people with severe community-acquired pneumonia. Based on the evidence and taking account of the principles of antimicrobial stewardship, the committee agreed that oral antibiotics should be given first line for most children and young people, unless they cannot take oral medicines (for example, if they are vomiting), or the severity of infection means that intravenous antibiotics are required. Based on its experience, the principles of antimicrobial stewardship and supported by the evidence in children and young people, the committee agreed that oral antibiotics should also usually be given first line for adults. For people with non‑severe symptoms or signs, intravenous antibiotics may be required if the person is unable to take oral medicines. In line with the NICE guideline on antimicrobial stewardship and Public Health England's Start smart – then focus, the committee agreed that if intravenous antibiotics are used initially, this should be reviewed by 48 hours (taking into account the person's response to treatment and any microbiological results) and switched to oral treatment where possible.# Other considerations # Medicines adherence Medicines adherence may be a problem for some people taking antibiotics that need frequent dosing or longer treatment duration. See the NICE guideline on medicines adherence. # Resource implications Recommended antibiotics are all available as generic formulations. See the Drug Tariff and the BNF for costs. See the evidence review for more information.

Metastatic calcification # Overview Metastatic calcification is deposition of calcium salts in otherwise normal tissue, because of elevated levels of calcium and other minerals in blood because of deranged metabolism, synthesis or disposal. It occurs as opposed to dystrophic calcification where blood levels of calcium are normal. Metastatic calcification can occur widely throughout the body but principally affects the interstitial tissues of the vasculature, kidneys, lungs, and gastric mucosa. Dystrophic calcification occurs in necrotic tissue with normal serum calcium levels; metastatic calcification occurs in normal tissue and requires elevated serum calcium levels. # Pathological Findings Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology - This is a gross photograph of the cut section of the patient's lung showing evidence of severe metastatic calcification. The lung tissue has a rough, firm appearance with open airways. - This low-power photomicrograph of the patient's lung illustrates large, open alveolar spaces. The pleural surface is the curved surface at the top. - A higher-power photomicrograph shows a blood vessel cut in longitudinal section (1). Several of the alveoli are filled with a pink-staining proteinaceous fluid (2) indicative of pulmonary edema. The alveolar septa and the wall of the blood vessel have a purplish color due to massive deposition of mineral (primarily calcium) in these tissues (3). - This high-power photomicrograph of a blood vessel shows calcium deposits in the vascular wall (1) and proteinaceous material (2) (from edema) within some of the alveoli. The smooth muscle in the vessel wall has been almost completely replaced by calcium deposits. - This photomicrograph demonstrates pulmonary alveoli with extensive calcium depositions (1) in the septa and protein accumulations (2) in the alveoli. Metastatic pulmonary calcification

1) All patients being considered for therapy should undergo a bone marrow aspiration and biopsy as well as peripheral blood films to establish a diagnosis and prognosis. a. Immunophenotyping by flow cytometry should be performed for diagnosis and to determine a leukemiaassociated immunophenotype (LAIP) if possible. b. Samples should also be sent for cytogenetics, including fluorescence in-situ hybridization (FISH) where appropriate. c. Molecular analysis should be sent. 2) Ancillary Tests: a. Organ function should be assessed including liver, kidneys, coagulation and cardiac function. b. Blood group and human leukocyte antigen (HLA) typing of patient and family should be done as soon as possible in transplant eligible patients. 3) A lumbar puncture, with the installation of intrathecal chemotherapy, should be performed if worrisome unexplained neurological symptoms are present without a mass lesion by imaging. a. Consider a screening lumbar puncture in cases of myelomonocytic or monocytic acute myeloid leukemia (AML) or in those with a presenting white cell count of >40 x 10 9 /L. 4) AML classification and risk stratification and transplant eligibility should be ascertained for all patients using age, performance status, World Health Organization (WHO) classification, cytogenetic and molecular risk group, as well response to therapy including minimal residual disease when possible. In the appropriate situations, establishing whether a genetic change is germline should be pursued. 5) Supportive care: a. In patients undergoing intensive chemotherapy a central venous catheter ideally should be placed. b. Red blood cell transfusions for symptomatic anemia. c. Platelets should be transfused at a threshold of 10 x 10 9 /L if there is no evidence of bleeding or to keep a platelet level of around 50 x 10 9 /L if there is active bleeding. d. Tumor lysis prophylaxis should be initiated in all patients. e. Antifungal prophylaxis should be considered during all phases of chemotherapy. f. Therapy of febrile neutropenia should include empiric broad spectrum antibiotics according to IDSA guideline. g. The use of growth factor support should be individualized. h. Steroid eye drops are recommended during the administration of intermediate to high dose cytarabine. These patients should also be screened for cerebellar toxicities before each dose of cytarabine. i. Sperm preservation should be discussed with male patients and a serum pregnancy test should be performed in female patients. 6) In transplant eligible patients treatment consists of induction and consolidation chemotherapy along with a FLT3 inhibitor in FLT3 positive cases a. Induction chemotherapy should consist of standard-dose cytarabine with an anthracycline b. Consolidation can consist of further cycles of chemotherapy alone or in association with a hematopoietic stem cell transplant depending on risk of relapse. i. Good riskchemotherapy alone. ii. Intermediate riskconsider transplantation. iii. High risktransplantation. 7) In transplant ineligible patients treatment options consist of palliation, low dose cytarabine, azacitidine or induction chemotherapy, depending on performance status and risk stratification. Strong consideration should be given to enrollment into a clinical trial. 8) In the instance of relapse re-induction chemotherapy can be considered depending on performance status, otherwise palliation should be instituted.# Participation of members of the Alberta Provincial Hematology Tumour Team in the development of this guideline has been voluntary and the authors have not been remunerated for their contributions. There was no direct industry involvement in the development or dissemination of this guideline. CancerControl Alberta recognizes that although industry support of research, education and other areas is necessary in order to advance patient care, such support may lead to potential conflicts of interest. Some members of the Alberta Provincial Hematology Tumour Team are involved in research funded by industry or have other such potential conflicts of interest. However the developers of this guideline are satisfied it was developed in an unbiased manner. # BACKGROUND Acute myeloid leukemia (AML) is a group of infrequent neoplasms responsible for a significant number of cancer-related deaths. Its incidence has been relatively stable over the last years at about 3.7 per 100 000 persons per year in the western world. It is primarily a disease of later adulthood with an increasing incidence with age. The median age at diagnosis is 65 years with a slight male preponderance. Outcome varies greatly according to age at diagnosis due to disease and patient features. Untreated AML is a uniformly fatal disease with a median survival of 11-20 weeks 1 . The etiology of AML in most cases is unclear. Known risk factors include exposure to chemotherapeutic agents particularly alkylating agents, topoisomerase-II inhibitors and anthracyclines as well as both therapeutic and nontherapeutic radiation. A higher than average incidence is seen in individuals with Down's syndrome, Klinfelter's syndrome, Ataxia telangectasia, Kostmann syndrome, neurofibromatosis or Fanconi anemia. Exposure to benzenes, pesticides, herbicides and cigarette smoking may also play a role in its development. There is also a greater incidence of AML in individuals with pre-existing hematologic disorders such as the myelodysplastic syndromes or myeloproliferative disorders. # GUIDELINE GOALS AND OBJECTIVES - To delineate the diagnostic criteria for acute myeloid leukemias To delineate the prognostic markers in acute myeloid leukemias To identify the management options for acute myeloid leukemias in adults including chemotherapy, hematopoietic stem cell transplantation, and palliation # GUIDELINE QUESTIONS - What is the optimal management of the acute myeloid leukemias in Alberta at the present time? # DEVELOPMENT AND REVISION HISTORY This guideline was reviewed and endorsed by the Alberta Provincial Hematology Tumour Team. Members of the Alberta Provincial Hematology Tumour Team include hematologists, medical oncologists, radiation oncologists, nurses, hematopathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Hematology Tumour Team and a Knowledge Management Specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook. This guideline was originally developed in 2008. This guideline was revised in 2015, 2017, 2018 and 2019. # SEARCH STRATEGY The original guideline (2008) was generated using systematic literature searches of the Pubmed and Medlinedatabases, ASCO abstracts and proceedings, and ASH abstracts and proceedings databases. The search included practice guidelines, systematic reviews, meta-analyses, randomized controlled trials and clinical trials. The 2015, 2017, 2018 and 2019 updates involved review of the Pubmed and Medline databases for relevant information on a topic-by-topic basis. The ASH, ASCO and EHA abstracts and proceedings databases were also screened. # TARGET POPULATION The following guidelines apply to adults over the age of 18 years. Different principles may apply to pediatric patients. # DISCUSSION # Diagnosis AML describes a heterogeneous group of clonal hematopoietic progenitor cell disorders with a spectrum of morphologic, immunophenotypic, cytogenetic and molecular characteristics. For a diagnosis of AML, a marrow blast count of ≥ 20% is required, except for AML with the recurrent genetic abnormalities t(15;17), t(8;21), inv (16) or t (16;16) and some cases of erythroleukemia. # Diagnostic Tests: The diagnosis is often suspected and can at times be confirmed from the peripheral blood. However, all patients being considered for therapy should undergo a bone marrow aspiration and biopsy. Samples should be sent for morphology, flow cytometry, cytogenetics and molecular analysis. Immunophenotyping by flow cytometry confirms myeloid lineage and stage of differentiation of the malignant cell. It may have a prognostic role by establishing a unique phenotype for minimal residual disease monitoring, the leukemia associated immunophenotyped (LAIP). A full karyotype will be determined at diagnosis in all cases. Fluorescence in-situ hybridization (FISH) will also be carried out in cases morphologically suspicious for specific subsets. Molecular analysis will be carried out in cases suspicious for promyelocytic leukemia looking for the PML/RAR, in the core binding factor leukemias looking for c-KIT mutations, as well as in cases with normal karyotypes looking for FLT3, NPM1 and CEBPA mutations. Information regarding FLT3-ITD allelic burden should also be provided. Next generation sequencing (NGS) should be performed at diagnosis, particularly in patients being treated with curative intent, with a panel that includes these genes as well as RUNX1, TP53, KIT and ASXL1 (see below). If there is no aspirate sample obtained the ancillary studies should be attempted on a peripheral blood sample. NGS is also available on a case by case basis in relapsed or elderly patients. Results of FLT3 testing must be available by day 8 of initiation of induction chemotherapy (allelic burden can be provided later). # Diagnostic Criteria: The threshold number of immature clonal cells, typically blasts, required to make the diagnosis of AML is 20% of total nucleated cells in the bone marrow by morphology. Exceptions include AML with t(8;21), inv(16), t(16;16) or t (15;17), in which the diagnosis of AML is made regardless of the percentage of bone marrow blasts 2 . De novo AML and acute erythroid leukemia should refer to patients with no clinical history of prior myelodysplastic syndrome, myeloproliferative disorder or exposure to potentially leukemogenic therapies or agents. Secondary AML should refer to patients with prior hematologic disease. Therapy related (t-AML) is a well-recognized clinical syndrome occurring as a late complication following cytotoxic therapy or radiotherapy for a primary neoplasm or a non-neoplastic disorder. # Epidemiological Distribution at Presentation: There are four main groups of AML recognized by the WHO classification system: AML with recurrent genetic abnormalities (11% of cases), AML with myelodysplasia-related features (6% of cases), Therapyrelated AML (2% of cases) and AML, not otherwise specified (81% of cases) 3,4 . AML can occur in people of all ages; however, it is most common in elderly patients. In rare circumstances AML can be caused by exposure to ionizing radiation and/or drugs that damage DNA. Anthracyclines and epipodophylloxtoxins which target topoisomerase II can lead to rapidly proliferative disease with monocytic histology and cytogenetic abnormalities at the MLL gene (11q23) months to 2 years after treatment 5 . Exposure to alkylating agents may lead to alkylator agent-induced disease, usually 5 to 6 years after exposure and characterized deletions in chromosomes 5 and 7 and by a myelodysplastic prodrome with complex karyotypes 6 . # Classification The blast count, lineage commitment, and level of differentiation of the neoplastic cells have long been the basis of AML classification. The WHO classification includes features such as genetic abnormalities at the chromosomal and/or molecular level and history of previous therapy or antecedent hematologic disease. The AML portion of the WHO classification of myeloid neoplasms was updated in 2016 3,7 . Table 1. Acute myeloid leukemia and related precursor neoplasms according to the WHO 2016 classification 3,7 . A lumbar puncture, with the installation of intrathecal chemotherapy, should be performed if worrisome unexplained neurological symptoms are present without a mass lesion by imaging. Consider a screening lumbar puncture in cases of myelomonocytic or monocytic AML or in those with a presenting white cell count of greater than 40 x 10 9 /L. The lumbar puncture should be done after clearing of peripheral blood blasts with platelet transfusion support as necessary. If done prior to blast clearance and there are blasts in the cerebrospinal fluid (CSF) the Steiherz/Bleyer algorithm should be applied to determine the CNS (central nervous system) status as per in acute lymphoblastic leukemia (ALL) 8 . Minimal residual disease (MRD) is defined as the persistence of leukemic cells after chemotherapy at numbers below the sensitivity detection level of routine morphology 10 . Typically detected by polymerase chain reaction or flow cytometry. Morphological leukemia-free stateless than 5% blasts in an aspirate sample with marrow spicules and with a count of at least 500 nucleated cells Morphological complete remission (CR) has been defined using the following criteria developed by an International Working Group 9,11,12 . # Definition of CNS Status - Normal values for absolute neutrophil count (>1000/µl) and platelet count (>100,000/µl), and independence from red cell transfusion o A bone marrow biopsy which is free from clusters or collections of blast cells. Extramedullary leukemia (i.e., central nervous system or soft tissue involvement) must be absent o A bone marrow aspiration reveals normal maturation of all cellular components (i.e., erythrocytic, granulocytic, and megakaryocytic series). There is no requirement for bone marrow cellularity o Less than 5% blast cells are present in the bone marrow, and none can have a leukemic phenotype (i.e., Auer rods). The persistence of dysplasia is worrisome as an indicator of residual AML but has not been validated as a criterion for remission status o The absence of a previously detected clonal cytogenetic abnormality (i.e., complete cytogenetic remission, CRc) confirms the morphologic diagnosis of CR but is not currently a required criterion. However, conversion from an abnormal to a normal karyotype at the time of first CR is an important prognostic indicator, supporting the use of CRc as a criterion for CR in AML 10,13,14 Complete remission with incomplete recovery (CRi) -All CR criteria are met, however, residual neutropenia (<1.0 x 10 9 /L or <1000/µl) or thrombocytopenia (<100 x 10 9 /L or <100,000/µl) Cytogenetic complete remission (CRc)this category is recommended primarily for use in clinical research studies but likely to be informative Molecular complete remissionrecognized as a therapeutic objective in acute promyelocytic leukemia but still controversial in other subsets Treatment Failure Resistant disease (RD) -Failure to achieve CR or CRi (general practice; phase II/III trials), or failure to achieve CR, CRi or PR (phase I trials); only includes patients surviving ≥7 days following completion of initial treatment, with evidence of persistent leukemia by blood and/or bone marrow examination Death in aplasia -Deaths occurring ≥7 days following completion of initial treatment while cytopenic; with an aplastic or hydroplastic bone marrow obtained within 7 days of death, without evidence of persistent leukemia Death from indeterminate cause -Deaths occurring before completion of therapy, or <7 days following its completion; or deaths occurring ≥7 days following completion of initial therapy with no blasts in the blood, but no bone marrow examination available Relapsea reappearance of leukemic blasts in the peripheral blood or greater than 5% blasts in the bone marrow not attributable to any other cause # Prognosis/Risk Stratification Several factors influence the ability to achieve and maintain a complete remission in acute myeloid leukemia. The most important of these are age and cytogenetic abnormalities (see Table 4 and 5). Molecular findings (Table 6) are also emerging as having important significance. There is some evidence from a small prospective study which indicates that the presence of minimal residual disease is associated with a significantly elevated risk of recurrence in patients with core binding factor AML 15 . MRD may also have a role in determining whether or not stem cell transplant is appropriate after achieving first remission 16 , however, further evidence is required. AML evolving from a myelodysplastic disorder or myeloproliferative disorder is often more resistant to cytotoxic chemotherapy than de novo AML. However, it may also have a more indolent course. The need for greater than one cycle of induction chemotherapy to achieve a complete remission is also considered a poor prognostic factor. # Age: Older patients have a higher prevalence of unfavorable cytogenetics and antecedent myelodysplastic/myeloproliferative disorders, higher incidence of multidrug resistance and an increased frequency of comorbid medical conditions that affect the ability to tolerate intensive treatment 17 . Even when standard chemotherapy is given outcomes are generally inferior to those achieved in younger patients 18 .Treatment related mortality often exceeds any expected transient response in this group. # Cytogenetics: Karyotype represents the single most important prognostic factor for predicting remission rate, relapse, and overall survival. Three groups of cytogenetic abnormalities have been defined with respects to these outcomes classified as favorable, intermediate and unfavorable risk. For example, in a retrospective review of 1213 (median age 52 years; 36% over age 60 years) AML patients treated on CALGB (Cancer and Leukemia Group B) protocols up to the year 2000, the 5-year survival rate was 55% for patients with favorable cytogenetics, 24% for patients with intermediate cytogenetics and 5% for those with poor risk cytogenetics 19 . This categorization holds whether the therapy includes stem cell transplantation or consolidation with chemotherapy alone . See table 4 for the cytogenetic classification. Cytogenetics at diagnosis retain their independent predictive value in the older AML patient population 25,26 . # Molecular Abnormalities: In addition to basic cytogenetic analysis, molecular markers are helping refine prognostic groups. These include FMS-like tyrosine kinase 3 (FLT3), c-KIT, nucleophosmin 1 (NPM1) and CEPBA. The most recent National Comprehensive Cancer Network (NCCN) guidelines recommend testing for these in all patients 29 . Recent European Leukemia Net (ELN) guidelines suggest testing as well for TP53, ASXL1 and RUNX1 30 . # FLT3 mutations The FLT3 gene encodes an enzyme (fms-related tyrosine kinase 3) which belongs to the type III receptor tyrosine kinase family, and is mutated in about 30% of AML patients 31,32 . FLT3 is expressed on the cellular surface and plays a role in proliferation, survival, and differentiation of hematopoietic progenitor cells 33 . FLT3 internal tandem duplication (FLT3-ITD) mutations, which are seen in approx. 25% of AML cases, are a strong poor prognostic factor, with higher relapse rates and inferior long-term survival in AML patients, even with high-dose chemotherapy and allogeneic hematopoietic stem cell transplant 31,32, . The FLT3-ITD allelic burden also has an impact on prognosis; patients with a high allelic burden, as defined by a mutant:wild type ratio of > 0.5, have a very high relapse rate and therefore constitute an adverse prognosis group. In contrast, those with a low allelic burden (mutant:wild type ratio < 0.5) have a relatively more favourable prognosis, particularly in the presence of a co-existing NPM1 mutation, and fall into an intermediate risk category . FLT3-tyrosine kinase domain (TKD) point mutations are seen in approx. 5% of cases; the prognostic value of this mutation is less clear, but it does not clearly appear to have a poor prognostic value 45 . The development of FLT3 inhibitors has been an area of much interest and promise . The multikinase inhibitor midostaurin has been shown to increase complete remission rates and overall survival in FLT3 mutated patients when used in combination with 7 + 3 chemotherapy and HiDAC (high dose cytarabine) consolidation starting on day 8 of induction chemotherapy 49 . It has now been approved and is considered standard of care for AML patients with FLT3 mutations undergoing induction chemotherapy. FLT3 mutation analysis must therefore be available to act upon by day 8 after the initiation of induction chemotherapy. # NPM1 mutations Nucleophosmin 1 also nucleolar phosphoprotein B23 or numatrin is encoded by the NPM1 gene which is mutated in approximately 45-64% of cytogenetically normal AML patients. NPM1 mutations lead to abnormal cytoplasmic localization of the protein, which typically functions as a chaperone in the nucleoli and acts in the control and regulation of the ARF-p53 tumor suppressor pathway. The NPM1 mutation in AML patients is a favourable prognostic factor, associated with overall survival and relapse-free survival of approximately 60% . However, this effect is mitigated by the presence of co-existing FLT3-ITD, and possibly by DNMT3A mutations, although there are conflicting data regarding the latter 60,61 . The presence of a co-existing low allelic burden FLT3-ITD lowers the survival to approx. 40%, while a high allelic burden FLT3-ITD lowers survival to 20-30% . c-KIT mutations c-KIT is a receptor tyrosine kinase which is expressed in 60-80% of myeloblasts 62 . It activates an important signaling pathway mediating cell proliferation and survival. c-KIT mutations are rare in most AML subtypes but are present in approx. 30% of core binding factor (CBF) AML, which includes t(8;21) and inv( 16); these cases are associated with a higher relapse rate compared with non-c-KIT mutated CBF . Because of this, these patients are frequently referred for allogeneic HSCT in first CR. However, a recent French GRAALL study found that, incorporating MRD testing post-cycle 2 of chemotherapy by qRT-PCR (see below) into a multivariate analysis, c-KIT mutation status was not an independent prognostic factor for relapse 66 . Therefore, if MRD monitoring is available, patients who achieve a >3 log reduction in RUNX1-RUNX1T1 or CBFB-MYH11 transcripts by qRT-PCR at the end of the second chemotherapy cycle could be serially monitored by qRT-PCR, without transplant. # CEBPA mutations The CCAAT/Enhancer Binding Protein α (CEBPA) gene encodes a transcription factor which is mutated in 10-15% of AML patients, mostly with normal cytogenetics or 9q deletion 67,68 . Three different mutation patterns are typically reported in AML patients: (i) A single mutated allele (single mutation CEBPA, therefore heterozygous with wild type) (CEBPAsm) representing approximately 50% of CEPBA mutated AML cases. (ii) AML with two CEPBA mutations (double-mutated, typically biallelic, no wild type CEBPA expression (CEBPAdm). (iii) AML carrying a homozygous CEBPA mutation due to loss of heterozygosity (no wild type CEPBA expression) 69,70 . Favourable prognosis in CEBPA-mutated AML patients is typically restricted to those cases with biallelic CEBPA in the absence of other cytogenetic aberrations or FLT3-ITD 57,71 . The favourable prognosis associated with biallelic CEBPA mutations is mitigated by FLT3-ITD mutations 71,72, , although it is unclear whether this applies to all such mutations or only those with higher FLT3 allelic burden. Other mutations RUNX1 and AXSL1 mutations, each occurring in 10-15% of AML patients, have each been associated with adverse prognosis, particularly when occurring in intermediate risk disease, and these patients appear to benefit from transplant in CR1 . Similarly, TP53 and splicing factor mutations (e.g. SRSF2) have also been associated with independently adverse prognosis 77 . RUNX1, ASXL1 and TP53 mutated disease have been assigned to the adverse risk group in the 2017 ELN classification, except when they occur in otherwise ELN favourable risk disease 30 . Therefore, this mutational information can be helpful in risk stratification. With respect to other mutations (e.g. DNMT3A, IDH, TET2) the data regarding prognosis are less clear. # Germline mutations It is now recognized that patients with certain inherited mutations carry a higher risk of developing AML and other myeloid neoplasms; some of these can be detected in standard myeloid panels. These include RUNX1, GATA2 and CEBPA 78 . Detection of one of these mutations in a younger patient should prompt germline mutation testing, using non-hematopoietic tissues such as buccal swabs or cultured fibroblasts. If a germline mutation is detected, any potential sibling donor should be tested, as this would present a theoretical risk of the donor marrow developing leukemia. TP53 mutations (as seen in Li-Fraumeni syndrome) predispose patients to the early development of a number of solid tumour malignancies; these patients are also at higher risk of developing AML or MDS with exposure to chemotherapy or radiation 78 . Therefore, detection of a TP53 mutation in patients with such a history should also prompt consideration of germline mutation testing. 80 The true prevalence of myeloid neoplasms with germline predisposition is uncertain, based largely on a lack of available population data; the WHO nevertheless describes these as relatively rare 80 . Despite the likely low prevalence of predisposing mutations in the general population, recent next-generation sequencing data suggest that germline mutations may be found in as many as 8.4-11.6% of AMLs and 12.9% of MPNs 81 , which would equate to one in every 5-10 patients with a new diagnosis. There is vast variation in germline mutation prevalence by subgroup, however; Down syndrome associated AML, for example, accounts for up to 14% of pediatric cases of AML 82 , whereas DDX41 germline mutations are observed in an estimated 1.4% 83 . There are also notable differences in malignancy penetrance by germline event: the relative risk of development of a myeloid malignancy in patients with germline CEBPA mutations is estimated to be near complete, for example, whereas the risk of AML in patients with Dyskeratosis Congenita is far lower 80,84 . Finally, variable age of onset of disease may be seen across the entities: patients with bone marrow failure syndromes may develop malignancies in early adulthood, whereas the mean age of onset of disease in patients with germline DDX41 mutations is the seventh decade 80 . Population-based screening for germline mutations associated with increased risk of myeloid malignancies is not currently feasible, however advanced molecular testing might be considered in certain settings. Clinical suspicion for a myeloid neoplasm with germline predisposition may arise by way of specific clinical features: Personal history of multiple cancers Thrombocytopenia, bleeding propensity or macrocytosis preceding the diagnosis of a myeloid neoplasm by several years A first or second degree relative with a hematological neoplasm A first or second degree relative with a solid tumor suggestive of germline predisposition (e.g. early-onset breast cancer) Physical exam features compatible with an inherited condition Failure of a potential stem cell donor to mobilize using standard protocols Modified from 80,85 The possibility of germline predisposition might also arise in cases of myeloid neoplasia with specific mutational profiles, and some genetic changes cannot be discerned reliably as somatic or germline without confirmatory germline testing 86 . Variants in some genes established as germline predisposing factors may be acquired in the somatic context 86 . In the absence of tumor-normal paired testing (which is typical in hematologic neoplasms), germline variants tend to demonstrate heterozygous range variant burdens that remain fixed over time (and despite changes in tumor burden), tend not to be of high frequency in somatic mutation databases (with the potential for emphasis in germline variant databases), and tend to have specific functional implications 86 . Guidelines published by the American College of Medical Geneticists may be employed to assist in the assessment of a putative germline variant 87 . Patients considered high risk, either by clinical assessment or tumor-only variant profiling, should have confirmatory testing. In Alberta, comprehensive testing for myeloid neoplasms with germline predisposition is largely unavailable, and therefore the approach to confirmatory testing is mainly dictated by the putative gene or condition under consideration. If a patient is presenting with a possible bone marrow failure syndrome or aplastic anemia, recommended testing approaches are elaborated in a separate CKCM document ( ). These conditions require chromosomal breakage or telomere length studies (the latter performed in British Columbia). Confirmatory testing by next-generation sequencing for possible Fanconi Anemia is available through AHS Genetics & Genomics, however the common genetic variants associated with Dyskeratosis Congenita are not available as part of the AHS Genetics & Genomics comprehensive germline testing panel. Similarly, this panel can provide testing for CEBPA, GATA2 and RUNX1, however the panel does not include test features for DDX41, ANKRD26, or ETV6. Testing using the AHS Genetics & Genomics comprehensive germline testing panel requires a specific requisition ( ). Send out testing to address the above genes not interrogable in Alberta must be organized through AHS Genetics & Genomics ( ); the University of Chicago offers a comprehensive familial myelodysplastic syndrome/acute leukemia panel ( ) Patients with an established familial germline predisposition syndrome should not be worked-up using comprehensive panels. Instead, testing tailored to the specific variant of interest should be organized through AHS Genetics & Genomics. Determining if a genetic abnormality is germline or if a predisposing condition exits is important for genetic counselling with respects to other family members. It becomes particularly important if a hematopoietic stem cell transplant is being considered and donors are being sought within the family. In some rare instances such as Faconi anemia and Li Fraumeni syndrome (germline TP53 mutation) conditioning for the transplant would need to be altered to avoid excessive toxicity. # Minimal (measurable) residual disease Early response to therapy is one of the most important prognostic factors in acute leukemia. Evaluation of minimal or measurable residual disease (MRD) is critical to identify patients at elevated risk of relapse which influences clinical decision-making. The leukemia associated immunophenotype (LAIP) of each patient should be established at diagnosis by multiparameter flow cytometry (MPFC), particularly if there is not a molecular abnormality to follow. Analysis of MRD by a properly validated technique performed locally is then recommended to be followed regularly by bone marrow aspirate until negative or the patient proceeds to transplantation. A study in de novo (n=126) AML evaluated the utility of MRD in predicting relapse. Patients were segregated by their detectable levels of cells with LAIP at the remission determination bone marrow. The patients were split into very low risk (n=8), defined as having fewer than 10 -4 LAP cells per sample, low risk (n=37), defined as having 10 -4 to 10 -3 LAP cells per sample, intermediate risk (n=64), defined as having fewer than 10 -3 to 10 -2 LAP cells per sample, and high risk (n=17), defined as having greater than 10 -2 LAP cells per sample. No patients from the very low risk category relapsed during the time observed, whereas 14%, 50% and 84% of patients in the low, intermediate and high-risk group relapsed after 3 years, respectively (p=0.0001). Additionally, there were significant differences in overall survival (OS) between groups, with 100%, 90%, 62% and 29% rates after 3 years of follow-up (p= 0.003) 88 . Another study, by Perea and colleagues, evaluated the prognostic value of MRD amongst AML patients with favorable cytogenetics (t(8;21) and inv( 16)) (n=55). MRD was evaluated by tandem RT-PCR (reverse transcription polymerase chain reaction) and flow cytometry. The group found that the mean amount of MRD detected by flow cytometry at the end of treatment in relapsed vs non-relapsed patients was significantly different (0.3% vs 0.08%, respectively; p=0.002) 89 . In a prospective, blinded study of pediatric patients (n=252) with de novo AML employing a multivariate analysis controlling for allogeneic marrow transplantation, age, sex, white blood count at diagnosis, presence of splenomegaly or hepatomegaly, and presence of more than 15% blasts in the marrow after the first course of induction (by flow cytometry), showed that patients with MRD, defined as ≥0.5% blasts, after one induction and one consolidation were 4.8-fold more likely to relapse (p<0.001) and 3.1-fold more likely to die (p< 0.001) when compared to MRD-negative patients 90 . A large multi-center prospective study (n=471) was designed to determine cut-off points for MRD in determining relapse rates. MRD was tested after induction cycle 1, cycle 2, and consolidation treatment in age 0.1% after induction cycle 1 and after two cycles of chemotherapy, there was a significant increases in relapse rates compared to those with lower or undetectable MRD levels. On multivariate analysis, MRD positivity after cycle 2 remained an independent prognostic factor for relapse 91 . Another prospective study (n=892) reporting findings from the United Kingdom National Cancer Research Institute AML 16 Trial evaluated the prognostic utility of MRD in elderly patients. MRD negativity amongst patients who achieved CR, was reported in 51% (n=286) of patients after first treatment, and 64% (n= 279) of patients after the second treatment, which was associated with a significantly better 3-year survival (p < 0.001 for both) and a significantly lower relapse rate (p< 0.001 for both) when compared to MRD-positive patients. Higher risk of early relapse was also reported amongst MRD-positive patients (median time to relapse 17.1 vs 8.5 months in MRD-negative patients) 92 . A retrospective study sought to investigate the prognostic utility of MRD in pre-hematopoietic cell transplant (HCT) patients. The study consecutively enrolled patients (n=99) receiving myeloablative HCT for AML in first morphologic remission. MRD was defined as any detectable level of residual disease. Two-year overall survival was 30.2% amongst MRD-positive patients versus 76.6% in MRD-negative patients and two-year relapse rates were 64.9% amongst MRD-positive patients versus 17.6% in MRDnegative patients. After adjustment for all or a subset of cytogenetic risk, secondary disease, incomplete blood count recovery, and abnormal karyotype pre-HCT, MRD-positive HCT was associated with increased overall mortality (HR 4.05, 95% CI: 1.90 to 8.62; p <0.001) and relapse (HR 8.49, 95% CI 3.67 to 19.65; p <0.001) when compared to MRD-negative HCT 93 . A subsequent report confirmed the poor prognosis and high relapse rate of patients with MRD detectable disease by MPFC just prior to transplant 160 . Molecular studies by quantitative RT-PCR can also be used for detection of MRD, with a sensitivity of 1 in 10 -4 cells. The value of RT-PCR in core binding factor AML has already been discussed. NPM1 mutations can also be monitored by this technique 94,95 . A study by the UK NRCI found that persistence of detectable NPM1 transcripts after the second cycle of chemotherapy was associated with a higher risk of relapse (82% vs. 30%; hazard ratio, 4.80, P 0.1% detectable disease by MPFC, following the second cycle of intensive chemotherapy (e.g. one induction and one consolidation) have high relapse rates. In these cases, consideration should be made to altering therapy. It was also recommended that serial monitoring by qRT-PCR be considered for those patients with RUNX1-RUNX1T1, CBFB-MYH11 or NPM1 who are not proceeding to transplant. Not all of these tests are currently routinely available or uniformly reported in Alberta; our goal is to work toward implementing standardized MRD testing, based on these guidelines. A recent study found that mutational profiling by NGS can also be used for MRD detection postchemotherapy, and can be predictive of relapse 97 , however, this is not currently recommended for MRD assessment outside of clinical trials. Defined by the presence of one single monosomy (excluding loss of X or Y) in association with at least one additional monosomy or structural chromosome abnormality (excluding core-binding factor AML). g. These markers should not be used as an adverse prognostic marker if they co-occur with favorable-risk AML subtypes. h. TP53 mutations are significantly associated with AML with complex and monosomal karyotype. # Risk Groups as per Cytogenetic and Molecular Status Treatment 29,98,99 The initial goal of therapy for AML is to achieve a complete remission, given that a complete remission with currently available therapy is requisite, although not sufficient for a cure. It is the sole outcome currently associated with improved survival. Chemotherapy is the mainstay of treatment. Poor performance status and comorbid medical conditions, in addition to age, are factors which influence the ability of an individual to tolerate induction therapy. In patients undergoing intensive chemotherapy a central venous catheter ideally should be placed. Supportive care in all patients includes red blood cell transfusions for symptomatic anemia. Platelets should be transfused at a threshold of 10 x 10 9 /L if there is no evidence of bleeding or to keep a platelet level of around 50 x 10 9 /L if there is active bleeding. Tumor lysis prophylaxis with allopurinol should be initiated in all patients. Monitoring for electrolyte abnormalities and renal function should be ongoing during the first few days of induction chemotherapy particularly in patients with significantly elevated white blood cell count. Rasburicase should be considered in those at high risk of significant tumor lysis. Antifungal prophylaxis should be considered during all phases of chemotherapy depending on local incidence of invasive fungal infections 29,98 . In a large randomized trial in AML patients receiving induction and post-remission chemotherapy, posaconazole prophylaxis was associated with a lower incidence of invasive Aspergillosis and lower mortality compared with fluconazole or itraconazole 100 . Therapy of febrile neutropenia should include empiric broad spectrum antibiotics according to IDSA guidelines 101 . The use of growth factor support should be individualized and should be considered in those with documented life-threatening infections. Recent use of G-CSF can increase the blast count in a bone marrow specimen obtained to determine remission status, however immunophentoyping may be useful in this situation if the leukemic cells are known to have an abnormal phenotype. Pegylated growth factors have not been studied in this setting. Steroid eye drops are recommended during the administration of intermediate to high dose cytarabine to prevent conjunctivitis. These patients should also be screened for cerebellar toxicities before each dose of cytarabine. Sperm preservation should be discussed with male patients and a serum pregnancy test should be performed in female patients. Women should be given their options regarding fertility preservation. Rare patients who present with extramedullary disease should be treated with systemic therapy. Local therapy (surgery/radiotherapy may be useful for residual disease). # Transplant Eligible Patients: # Induction Chemotherapy should consist of standard-dose cytarabine with an anthracycline, so called 7&3 chemotherapy (see appendix A for regimens). Studies looking at higher doses of cytarabine in induction have not shown an increased CR rate but have demonstrated an increased treatment related mortality . At count recovery or about day 28-35 from the start of chemotherapy a bone marrow aspirate should be done to determine remission status. The likelihood of establishing a CR with one cycle of induction chemotherapy varies amongst prognostic groups but overall is in the order of 60-70%. Consider repeating cytogenetic analysis if initially abnormal as part of the remission documentation 29 .Other regimens such as FLAG (fludarabine + high-dose cytarabine + G-CSF) or NOVE (mitoxantrone + etoposide) may need to be considered in the case of significant left ventricular dysfunction. # Re-induction If CR is not achieved after one cycle of induction chemotherapy another attempt is appropriate. This may consistent of a repeat of 7&3 chemotherapy or alternatively a different regimen such as NOVE, NOVE-HiDAC 80 , FLAG-Ida (FLAG + idarubicin), or high dose cytarabine (HiDAC) (see appendix A for regimens) may be tried. A bone marrow aspirate and biopsy should be done at count recovery or day 30-35 to document remission status. The likelihood of a second regimen being successful is in the order of 50%. If no remission is achieved after 2 cycles of induction chemotherapy palliation may become the goal of care. # Consolidation If CR has been achieved further therapy is necessary for potential cure. The nature of consolidation therapy must be individualized for each patient based on a risk analysis of the risk of relapse of the AML versus the risk of the proposed consolidation therapy. This will depend on prognostic features of the leukemia, response to therapy, performance status and type of hematopoietic stem cell donor available. HiDAC is the mainstay of consolidation chemotherapy as there has been shown to be a dose intensity effect to cytarabine suggesting that HiDAC is beneficial in induction or consolidation 103,104 . Generally at least one cycle is administered in all patients if only to allow for planning of an allogeneic stem cell transplant although the absolute need for this is controversial. - Good risk patients: In patients with AML with t(8;21) or inv 16, data suggests that provided there are no additional risk factors multiple cycles of HiDAC provide higher overall survival than lower doses of cytarabine or stem cell transplant .Our recommendation is 3-4 cycles of HiDAC post induction chemotherapy. A recent retrospective study from Edmonton and Vancouver found similar outcomes with 2 cycles of consolidation compared with 3 110 , but this requires confirmation in a prospective study. There is also evidence that the addition of gemtuzumab ozogamicin (GO) may produce better outcomes when combined with chemotherapy 111 ; however, this agent is not yet approved in Canada. - Intermediate risk patients: HiDAC has been shown to be preferable over lower dose cytarabine in this cytogenetic group as well 26,107 but its superiority over stem cell transplantation has not been established. It is generally recognized that an allogeneic stem cell transplant provides a decreased relapse rate at a cost of increased treatment related mortality when compared to consolidation chemotherapy or autologous transplantation 109, . The transplant related mortality gap between matched related and unrelated donors has been shown to be significantly reduced in recent years 115,116 . A suitable hematopoietic stem cell donor should be sought. If a matched sibling donor is found a related myeloablative stem cell transplant should proceed as soon as possible, ideally after one dose of HiDAC. If there are no suitable family donors, the patient should proceed through 3-4 cycles of HiDAC consolidation while a match unrelated donor is sought. If one is found before the third cycle of consolidation chemotherapy, consider matched unrelated donor stem cell transplantation. - High risk patients: All efforts should be undertaken to find a matched donor, related or unrelated for eligible patients. During that time the patient should receive ongoing cycles of HiDAC chemotherapy up to a total of 4 cycles. The patient should proceed to allogeneic stem cell transplantation as soon as a donor is identified. If no fully matched donor is available consideration should be given to a haploidentical related transplant if a suitable donor is available. Finally, unrelated cord blood transplantation is also an option in selected situations. # FLT3 Mutation Positive Patients: If not enrolled on a clinical trial with a FLT3 inhibitor, midostaurin should be added for these patients on day 8 of each induction and consolidation treatment cycle, as per the RATIFY clinical trial protocol (midostaurin and standard induction/consolidation chemotherapy). The Phase III RATIFY (CALGB 10603) trial randomized 717 AML patients with FLT3 mutation to receive standard induction and consolidation chemotherapy +/-midostaurin. After a median follow-up of 57 months, patients in the midostaurin arm had a significant improvement in median overall survival vs. placebo (74.7 months vs. 26 months, respectively; p=0.007), representing a 23% reduction in the risk for death 49 . It has now been approved by Health Canada for this indication. # Relapse: - Re-induction: An attempt at achieving a second CR should be attempted. If the remission was greater than one year 7&3 chemotherapy can be used again. Otherwise other regimens such as FLAG-Ida, NOVE, NOVE-HiDAC, or HiDAC are appropriate. Participation in a clinical trial is encouraged. - Hematopoietic stem cell transplantation: If a stem cell transplant was not done in first CR it should be undertaken once a second CR has been achieved. The ideal donor would be an allogeneic matched related or unrelated donor, or if necessary a related haploidentical donor or cord blood unit. # Palliation If comorbid conditions affect the ability to proceed with optimal aggressive therapy, treatment with either low-dose cytarabine (LDAC) or azacitidine (VIDAZA®) is recommended as these have been shown to increase overall survival compared to supportive care alone 117,118 . Azacitidine is recommended for patients with 20-30% marrow blasts with dysplasia and for patients with adverse risk cytogenetics, based on two Phase III randomized trials 119,120 . For patients with >30% blasts and intermediate risk cytogenetics, LDAC and azacitidine have similar survivals 121 ; LDAC has the advantage of lower cost and the potential for athome administration. The recommended dose of azacitidine is 75 mg/m 2 /day subcutaneously for 7 days, every 28 days, for at least six cycles 122 . This is also an appropriate approach in the setting of primary induction failure not eligible for further intensive therapy, or relapse, particularly after allogeneic stem cell transplantation. It may also be considered in patients in CR after induction where aggressive chemotherapy for consolidation is no longer indicated. The most commonly used dosing for LDAC is 20 mg subcutaneously twice daily for 10 days 117 , repeated every 4-5 weeks; 40 mg once daily may be used for home care administration. At least 4 cycles should be used, unless there is clear evidence of progression earlier. In patients not responding to LDAC, azacitidine may be utilized; however, LDAC does not appear to be effective in azacitidine failures. For patients not able or willing to receive these treatments, or not responding to these, supportive care alone is appropriate, with hydroxyurea to control circulating blast counts. Transplant Ineligible Patients: In patients with a normal karyotype, the remission rate on older patients is 50-60% with cytarabine combined with idarubicin, daunorubicin or mitoxantrone. In those with adverse risk cytogenetics the chance of achieving a remission is approximately 25%, with median OS of approximately 6 months 25,26,123 . Attempts to modify this by adjusting the chemotherapy regimens, adding growth factors or multidrug resistance protein regulators have not been successful 17, . Due to the poor outcomes in this group, clinical trials are particularly important. However, if none are available, azacitidine would be appropriate therapy in older patients with high-risk cytogenetics who are not considered candidates for allogeneic HSCT. In other elderly non-fit patients, low-dose cytarabine would also be appropriate # Induction In patients with an ECOG performance status of 2 or less and no prohibitive comorbid conditions, standard 7&3 induction chemotherapy is appropriate 127 , particularly in patients with core-binding factor leukemias. If consideration is being given to consolidation therapy or re-induction in the case of primary induction failure, a bone marrow aspirate should be performed to document remission. If no further therapy is planned this can be omitted. # Consolidation Consolidation chemotherapy in this group of patients is controversial. There is evidence to suggest that low-dose, prolonged ambulatory treatment should be preferred to intensive chemotherapy 123 ; however intermediate dose cytarabine can be considered if the patient maintains a good performance status, normal renal function, and has a good or normal karyotype. Consolidation has not been shown to prolong survival in patients with high risk karyotypes. There is limited retrospective data which suggests azacitidine may be appropriate in this setting, although prior cytotoxic therapy was associated with a decreased marrow response rate, azacitidine treatment still prolonged overall survival 128 . LDAC may also be considered in patients in CR who are not suitable candidates for further intensive chemotherapy. # Relapse In this age group, if acute leukemia recurs palliation with best supportive care or azacitidine is indicated if there are no available clinical trials. # Mixed-Phenotype Acute Leukemia: Mixed-phenotype acute leukemia (MPAL) is rare, accounting for less than 5% of acute leukemia cases 7 . Treatment approaches to MPAL vary, as there is no standard therapy for patients. Typical, treatment may include AML-type induction therapy, ALL-type induction therapy, or a hybrid combination of AML/ALL-type induction regimen 129 . An early allogeneic hematopoietic cell transplant should be considered for these patients. It should be noted that data regarding the treatment of MPAL is largely retrospective in nature, with limited studies available for review. One international retrospective study of 100 children and adults with MPAL defined by the 2008 WHO classification reported a 5-year survival rate of 37% (median survival 1.5 years) 130 . Treatment was selected by the managing physician and information regarding the treatment choice by age group was not presented. Age >15, Philadelphia chromosome positive leukemia, and AML-type induction treatment approaches were associated with significantly reduced median survival. Data from this study is summarized below. , however, it remains unclear whether all of these risk factors still apply to patients treated with modern induction regimens. Symptoms of increased intracranial pressure, cranial nerve palsies, symptoms of CNS hemorrhage, symptoms of spinal cord compression and/or visual changes indicate potential CNS involvement. Mass lesions are uncommon, although reported at a higher frequency in inv( 16) patients 132 . Diagnosis of CNS leukemia is typically confirmed by the identification of leukemic blasts on cytocentrifuge preparations of cerebrospinal fluid after lumber puncture. No prospective studies comparing intrathecal chemotherapy, systemic chemotherapy and/or cranial radiation have been reported to guide treatment in patients with CNS leukemia. Intrathecal chemotherapy with methotrexate (12 to 15 mg/dose) or cytarabine (50-70 mg/dose) is a common approach. Systemic high dose methotrexate or cytarabine in combination with diaziquone has been shown to achieve clearance of the CNS tumour load 135 , however, even after successful therapy, treatment in this setting is associated with high relapse rates 136 . Patients with cranial nerve involvement or a tumour mass that impinges on important structures may require initial radiation therapy (18 to 25 Gy for the brain) followed by intrathecal chemotherapy 136,137 . In patients with neurological symptoms imaging should be done to rule out a mass or bleed. If neither of these is present a lumbar puncture should be done and sent for morphology as well as flow cytometry. If this is negative for leukemic cells initially it should be repeated if the symptoms persist. If it is positive, as per the diagnostic criteria in section 3, intrathecal chemotherapy should be administered twice a week concurrently with induction chemotherapy until the cerebrospinal fluid is no longer positive by morphology and flow cytometry. An additional 2 intrathecal treatments should then be administered. Intrathecal chemotherapy should consist of alternating single agent cytarabine and methotrexate or "triple therapy" with cytarabine, methotrexate and hydrocortisone. In patients with myelomonocytic or monocytic leukemia as well as those with a presenting blast count of greater than 40 x10 9 /L consider a screening lumbar puncture at diagnosis with intrathecal chemotherapy administered at the same time. If the cerebrospinal fluid is positive for leukemic cells the patient should be treated as above. # Follow Up Once all therapy is completed no further bone marrow aspirates are indicated unless there is concern of relapse or loss of graft in transplanted patients. Regular complete blood counts should be performed every month for the first few years then every 3 months until 5 years. The risk of recurrence after 5 years is very low and hematological follow up can be stopped at that point. Patients should be reminded of the signs and symptoms of leukemia including those of anemia, thrombocytopenia and infection and instructed to seek medical attention at any point if these develop. If there is concern of a relapse at any point, a bone marrow aspirate and biopsy should be performed and the patient should be sent for all the appropriate diagnostic tests. # New Therapies Gemtuzumab ozogamicin (GO) the anti-CD33 antibody carrying a toxic calicheamicin-γ1 derivative, which after intracellular hydrolytic release, induces DNA strand breaks, apoptosis, and cell death was the first anti-cancer immunoconjugate to obtain regulatory approval in the United States. It was subsequently withdrawn from the US by Pfizer after results from the S0106 trial demonstrated no overall survival benefit, while reporting an increased rate of early mortality in the GO arm of patients 18-60 years old with de novo AML receiving 2 cycles of induction chemotherapy with daunorubicin/cytarabine with or without GO (6 mg/m 2 ) 105 . However, emerging data from other well controlled studies did report benefits from the addition of GO to chemotherapy, particularly when used in smaller fractionated doses . A recent metanalysis of 5 randomized trials found an overall survival benefit for GO when added to intensive chemotherapy, most strikingly seen in patients with favourable risk cytogenetics, while those with adverse risk karyotypes did not benefit 111 . In September 2017 GO was approved by the FDA for this indication. It is currently under review by Health Canada (February 2019) and available via compassionate access. CPX-351 (Vyxeos R ) is a nanoparticle formulation containing a fixed molar ratio of daunorubicin and cytarabine. A phase III randomized trial in previously untreated AML patients with secondary AML age 60-75 found that this agent was superior to standard 3+7 induction therapy 142 , while no benefit was seen in another study in de novo 143 . It has now been FDA approved for the treatment of secondary AML as of August 2017; approval in Canada is pending however it is available on a compassionate basis. The development of more potent second generation FLT3 inhibitors remains an area of active investigation. The second-generation inhibitors (quizartinib, gilteritinib, crenolanib) have produced CR rates in the 40% range as single agents in relapsed AML 144,145 , but remain investigational. These agents are being actively investigated in combination with chemotherapy, both in the frontline and relapsed setting. Gilteritinib is now available by compassionate access. Approximately 15-20% of AML patients have IDH1 or IDH2 mutations, which result in aberrant production of an oncoprotein, 5HG, which induces a block in cell differentiation. Enasidenib (AG221) is a selective oral IDH2 inhibitor that inhibits 5HG production and restores normal cell differentiation. Treatment with this agent in relapsed/refractory AML patients with IDH2 mutations has produced CR in approximately 30% of cases; responses may take up to 6 months to be seen 146 . This agent has now been approved by the FDA and Health Canada for this indication but not yet publically funded. It is available on a compassionate basis. Ivosidenib is a selective IDH1 inhibitor which has shown activity in IDH1 mutated disease in early clinical trials 147 . Another promising agent is venetoclax, a selective oral small molecule BCL-2 inhibitor. Although it has limited activity as a single agent, it has been found to synergize with chemotherapy agents in preclinical models. In a study by Wei et al, venetoclax 600 mg daily was given in combination with low dose cytarabine to patients with newly diagnosed AML not eligible to receive intensive induction chemotherapy 148 . Of the 82 patients evaluable, 44 (54%) achieved CR or CR with incomplete count recovery (CRi), demonstrating that this is an active combination in patients with newly diagnosed AML. Venetoclax in combination with azacitdiine or decitabine was evaluated in older patients with AML unfit to receive intensive chemotherapy. Of the 145 patients enrolled, 67%of patients achieved CR/CRi. The median duration of response was 11.3 months 149 . These regimens are now under evaluation in Phase III randomized clinical trials. Phase I studies are also ongoing adding it to intensive remission inducing chemotherapy. It has been approved by the FDA in patients over the age of 75 with de novo AML in combination with low dose cytarabine or hypomethylating agents as of November 2018. Many other novel agents are currently in clinical trials in AML, including agents that target MDM2 (inhibition of which results in upregulation of p53, inducing apoptosis) 150 , DOT1L (associated with MLL overexpression/rearrangements) 151 , Polo-like kinase-1 152,153 , and CXCR4 152,153 . A number of novel immunocongugates are also in clinical trials, targeting antigens expressed on AML stem cells such as CD123 and CLL1. CAR-T (chimeric antigen receptor) cell therapy is a novel form of immunotherapy which has produced remissions in many patients with chemotherapy-refractory ALL and lymphoma; early trials in AML are in progress. # MAINTENANCE A formal review will be conducted in 2019, however if new evidence is brought forward before that time, the guideline will be changed accordingly. # GLOSSARY OF ABBREVIATIONS Acronym

Hyperlipoproteinemia medical therapy # Overview Hyperlipidemia requires early detection, careful evaluation and aggressive treatment with combination of therapeutic lifestyle changes and lipid-lowering drug therapies to reduce the risk of cardiovascular and cerebrovascular complications. # Medical Therapy for Adults ## NCEP ATP III Recommendations for Medical Therapy of Hyperlipidemia in Adults ## Original Recommendations of the National Cholesterol Education Program (NCEP) ATP III for Medical Therapy of Hyperlipidemia in Adults (DO NOT EDIT) - Obtain complete lipid profile after 9 to 12-hour fast. ### Detect Presence of Coronary Heart Disease (CHD) Risk Equivalent - Previous personal history of clinical CHD - Clinical carotid artery disease - Abdominal aortic aneurysm - Peripheral arterial disease - Diabetes ### Determine Presence of Major Risk Factors (Other than LDL) - Hypertension (BP≥140/90 mmHg or on antihypertensive medication) - Cigarette smoking - Low HDL-cholesterol (<40 mg/dL) HDL-cholesterol ≥60 mg/dL counts as a "negative" risk factor and removes one risk factor from the total count. - HDL-cholesterol ≥60 mg/dL counts as a "negative" risk factor and removes one risk factor from the total count. - Age (men ≥45 years; women ≥55 years) - Family history of premature CHD in first degree relative (CHD in men <55 years; CHD in women <65 years) If 2+ major risk factors (other than LDL) are present without CHD or CHD risk equivalent, assess 10-year (short-term) CHD risk using Framingham Risk Score. The Framingham Risk Score is based on data obtained from the Framingham Heart Study. There are two Framingham Risk Scores, one for men and one for women. Three levels of 10-year risk: ### Determine Risk Category, LDL Goal of Therapy, Level for Therapeutic Lifestyle Changes (TLC), and Level for Drug Therapy ### Therapeutic Lifestyle Changes (TLC) Therapeutic lifestyle changes (TLC) should be initiated, if LDL level is above goal. - TLC diet - consists of saturated fat <7% of calories, cholesterol <200 mg/day, increased viscous (soluble) fiber (10-25 g/day), and plant sterols (2g/day) to enhance LDL lowering. - Weight management - Increased physical activity ### Drug Therapy Drug therapy should be initiated, if LDL exceeds levels shown in above table. Initiate drug simultaneously with TLC for CHD and CHD equivalents, whereas add drug to TLC after 3 months for other risk categories. (LDL=LDL cholesterol, HDL=HDL cholesterol, TG=Triglycerides) ### Treatment of Elevated Triglycerides - In case of hyperlipidemia with elevated triglycerides (≥150 mg/dL), primary aim of therapy is to reach LDL goal, intensify weight management and increase physical activity. - If triglycerides are ≥200 mg/dL after LDL goal is reached, set secondary goal for non-HDL cholesterol (total - HDL) 30 mg/dL higher than the LDL goal for respective categories. - If triglycerides are 200-499 mg/dL after LDL goal is reached, consider adding drug if needed to reach non-HDL goal: Intensify therapy with LDL-lowering drug Add niacin or fibrate to further lower triglycerides - Intensify therapy with LDL-lowering drug - Add niacin or fibrate to further lower triglycerides - If triglycerides are ≥500 mg/dL, first lower triglycerides to prevent pancreatitis: Very low-fat diet (<15% of calories from fat) Intensified weight management and increased physical activity Add niacin or fibrate When triglycerides reach <500 mg/dL, turn to LDL-lowering drug - Very low-fat diet (<15% of calories from fat) - Intensified weight management and increased physical activity - Add niacin or fibrate - When triglycerides reach <500 mg/dL, turn to LDL-lowering drug ### Treatment of Low HDL Cholesterol (<40 mg/dL) First reach LDL goal, intensify weight management, and increase physical activity; then if triglycerides are 200-499 mg/dL, achieve non-HDL goal and if triglycerides are <200 mg/dL (isolated low HDL) in CHD or CHD equivalent, add niacin or fibrate. ### Treatment of the Metabolic Syndrome - Identification of the metabolic syndrome (any 3 of the following): Abdominal obesity - waist circumference of >102 cm (>40 in) in men and >88 cm (>35 in) in women Serum triglyceride level ≥150 mg/dL HDL cholesterol level of <40 mg/dL in men and <50 mg/dL in women Blood pressure ≥130/85 mmHg Fasting glucose ≥110 mg/dL. - Abdominal obesity - waist circumference of >102 cm (>40 in) in men and >88 cm (>35 in) in women - Serum triglyceride level ≥150 mg/dL - HDL cholesterol level of <40 mg/dL in men and <50 mg/dL in women - Blood pressure ≥130/85 mmHg - Fasting glucose ≥110 mg/dL. - Treat underlying causes: Intensify weight management Increase physical activity. - Intensify weight management - Increase physical activity. - Treat lipid and non-lipid risk factors, if they persist despite TLC: Treat hypertension Use aspirin for CHD patients to reduce thromboembolic risk Treat elevated triglycerides and/or low HDL as shown above. - Treat hypertension - Use aspirin for CHD patients to reduce thromboembolic risk - Treat elevated triglycerides and/or low HDL as shown above. ## Other Lipid Lowering Agents ### Omega-3 Fatty Acids (↑ - Increase, ↓ - Decrease) ### Ezetimibe Ezetimibe is a new class of lipid lowering agents. It inhibits intestinal absorption of cholesterol. It has been approved as a monotherapy or in combination with statins to treat hypercholesterolemia. It has also been approved in combination with fenofibrate to treat mixed hyperlipidemia. # Medical Therapy in Children and Adolescents Click on the respective microchapter to read more about it: - Drug Therapy - Statins - Adjuvant Therapies # A Trial Based Approach to Statin Guidelines Shown below is a table suggesting an approach to the use of statin according to different trials.

Nontuberculous mycobacteria # Overview Non-tuberculous mycobacteria (NTM) are species other than those belonging to the Mycobacterium tuberculosis complex and do not cause leprosy. NTM are generally free-living organisms that are ubiquitous in the environment. There have been more than 150 NTM species identified to-date. They can cause a wide range of infections, with pulmonary infections being the most frequent. NTM are opportunistic pathogens and are abundant in the environment such as peat-rich potting soil and drinking water in buildings and households. Risk factors associated with pulmonary NTM are included but not limited to prior infection with TB, use of glucocorticoids and other immunosuppressive drugs, some pulmonary diseases such as bronchiectasis and cystic fibrosis (CF). # Historical Perspective - was first discovered by , a , in during/following . - In , mutations were first identified in the pathogenesis of . - In , the first was developed by to treat/diagnose . # Classification - NTM is most commonly classified by the growth rate, either slowly growing or rapidly growing: - Slow-growing mycobacteria are: Mycobacterium avium complex (includes avium and intracellulare species), M. kansasii, M. xenopi, M. simiae - Rapid-growing mycobacteria are: M. Abscessus, M. Fortuitium, M. Chelonae # Pathophysiology - The pathogenesis of is characterized by , , and . - The gene/Mutation in has been associated with the development of , involving the pathway. - On gross pathology, , , and are characteristic findings of . - On microscopic histopathological analysis, , , and are characteristic findings of . # Clinical Features # Differentiating nontuberculous mycobacteria from other Diseases - NTM lung disease must be differentiated from other chronic pulmonary diseases that cause chronic cough, shortness of breath and hemoptysis such as: - Tuverculosis - Histoplasmosis - Blastomyces - Silicosis - Pneumonia - Granulomatosis of lung # Epidemiology and Demographics - The prevalence of is approximately per 100,000 individuals worldwide. - In , the incidence of was estimated to be cases per 100,000 individuals in . ## Age - Patients of all age groups may develop . - is more commonly observed among patients aged years old. - is more commonly observed among . ## Gender - affects men and women equally. - are more commonly affected with than . - The to ratio is approximately to 1. ## Race - There is no racial predilection for . - usually affects individuals of the race. - individuals are less likely to develop . # Risk Factors - Common risk factors in the development of NTM lung disease are included but not limited to prior infection with TB, use of glucocorticoids and other immunosuppressive drugs such as TNF-alpha inhibitors, some pulmonary diseases such as bronchiectasis and cystic fibrosis (CF). # Natural History, Complications and Prognosis - The majority of patients with remain asymptomatic for . - Early clinical features include , , and . - If left untreated, of patients with may progress to develop , , and . - Common complications of include , , and . - Prognosis is generally , and the of patients with is approximately . # Diagnosis ## Diagnostic Criteria - The diagnosis of NTM pulmonary disease is made when at least three of the following diagnostic criteria are met: - Chest radiograph or, in the absence of cavitation, chest high-resolution computed tomography (HRCT) scan. - Three or more sputum specimens for acid-fast bacilli (AFB) analysis. - Exclusion of other diseases, such as tuberculosis (TB). ## Symptoms - Symptoms of NTM may include the following: - Chronic cough - Fatigue - Shortness of breath (dyspnea) - Coughing up of blood (hemoptysis) - Excessive mucus (sputum) production - Fever - Night sweats - Loss of appetite - Unintended weight loss. ## Physical Examination - Patients with usually appear . - Physical examination may be remarkable for: ## Laboratory Findings - There are no specific laboratory findings associated with . - A is diagnostic of . - An concentration of is diagnostic of . - Other laboratory findings consistent with the diagnosis of include , , and . ## Imaging Findings - There are two major radiological findings associated with NTM disease: Fibrocavitary and nodular bronchiectatic forms. - High resolution computed tomography (HRCT) is the imaging modality of choice for NTM lung disease. - On HRCT, the fibro-cavitary form of NTM is characterized by cavities with areas of increased opacity, usually located in the upper lobes, pleural thickening and volume loss by fibrosis with traction bronchiectasis are frequent. Unlike pulmonary tuberculosis, cavitation in NTM is thin-walled without lymph node calcification, no atelectasis and usually progresses more slowly. - HRCT of nodular bronchiectatic form may demonstrate bilateral, multilobar bronchiectasis, especially in the middle and lower lung fields, with small nodules. ## Other Diagnostic Studies - may also be diagnosed using . - Findings on include , , and . # Prophylaxis and Treatment of NTM Disease - Treatment and prophylaxis for NTM lung disease are based on the particular pathogens involved, the severity of the disease, (whether is cavitary or nodular/bronchiectasis), assessment of risks and benefits of therapy for individual patients. Treatment requires prolonged use of a combination of multiple drugs. - For the treatment of MAC pulmonary disease in most patients with nodular/bronchiectatic disease, a three-times-weekly regimen of clarithromycin (1,000 mg) or azithromycin (500 mg), rifampin (600 mg), and ethambutol (25 mg/kg) is recommended. For patients with cavitary MAC lung disease or severe nodular/bronchiectatic disease, a daily regimen of clarithromycin (500–1,000 mg) or azithromycin (250 mg), rifampin (600 mg) or rifabutin (150–300 mg), and ethambutol (15 mg/kg) with consideration of three-times-weekly amikacin or streptomycin early in therapy is recommended. Patients should be treated until culture negative on therapy for 1 year. - Treatment of disseminated MAC disease: Therapy should include clarithromycin (1,000 mg/d) or azithromycin (250 mg/d) and ethambutol (15 mg/kg/d) with or without rifabutin (150–350 mg/d). Therapy can be discontinued after the resolution of symptoms and reconstitution of cell-mediated immune function. - Prophylaxis of disseminated MAC disease: Prophylaxis should be given to adults with acquired immunodeficiency syndrome (AIDS) with CD4+ T-lymphocyte counts less than 50 cells/μl. Azithromycin 1,200 mg/week or clarithromycin 1,000 mg/day have proven efficacy. Rifabutin 300 mg/day is also effective but less well tolerated. - Treatment of M.kansasii pulmonary disease. A regimen of daily isoniazid (300 mg/d), rifampin (600 mg/d), and ethambutol (15 mg/kg/d). Patients should be treated until culture negative on therapy for 1 year. - Treatment of M.abscessus pulmonary disease. There are no drug regimens of proven or predictable efficacy for treatment of M.abscessus lung disease. Multidrug regimens that include clarithromycin 1,000 mg/day may cause symptomatic improvement and disease regression. Surgical resection of the localized disease combined with multidrug clarithromycin-based therapy offers the best chance for cure of this disease. - Treatment of nonpulmonary disease caused by RGM (M.abscessus, M.chelonae, M.fortuitum). The treatment regimen for these organisms is based on in vitro susceptibilities. For M.abscessus disease, a macrolide-based regimen is frequently used. Surgical debridement may also be an important element of successful therapy. - Treatment of NTM cervical lymphadenitis. NTM cervical lymphadenitis is due to MAC in the majority of cases and treated primarily by surgical excision, with a greater than 90% cure rate. A macrolide-based regimen should be considered for patients with extensive MAC lymphadenitis or poor response to surgical therapy. # Surgery - Surgical resection in conjunction with multidrug clarithromycin-based therapy is the most common approach to the treatment of localized M.abscessus lung disease. # Prevention - Effective measures for the primary prevention of NTM pulmonary disease include avoidance of exposure to NTM rich environments such as soil and water. Some experts believe that decreasing exposure to NTM organisms may be helpful preventive methods.

Childhood absence epilepsy Childhood absence epilepsy (CAE) is a subtype of idiopathic generalized epilepsy and is characterized by brief impairment of consciousness (absence seizure), typically without convulsions. The seizures appear between ages 3 and 12 and can occur multiple times per day. Patients are otherwise normal with no physical or neurological defects. Mutations in CACNA1H yield susceptibility for CAE and some mutations in GABRG2 yield susceptibility to CAE with febrile convulsions. # Signs and symptoms CAE is typified by absence seizures that are the first seizure type in the patient and begin between ages 3 and 12. These seizures occur numerous times per day and are associated with 3Hz spike-and-wave discharges bilaterally. # Causes CAE is a complex polygenic disorder. Particularly in the Han Chinese population there is association between mutations in CACNA1H and CAE. These mutations cause increased channel activity and associated increased neuronal excitability. Seizures are believed to originate in the thalamus, where there is an abundance of T-type calcium channels such as those encoded by CACNA1H. # Pathophysiology There are currently 20 mutations in CACNA1H associated with CAE. These mutations are likely not wholly causative and should instead be thought of as giving susceptibility. This is particularly true since some groups have found no connection between CAE and CACNA1H mutations. Many of the CACNA1H mutations have a measurable effect on channel kinetics, including activation time constant and voltage dependence, deactivation time constant, and inactivation time constant and voltage dependence (summarized in Table 1). Many of these mutations should lead to neuronal excitability, though others may lead to hypoexcitability. These predictions are due to mathematical modeling and may differ from what will occur in real neurons where other proteins, some of which may interact with CACNA1H, are present. Along with mutations in CACNA1H, two mutations in the gene encoding a GABAA receptor γ subunit are also associated with a CAE like phenotype that also overlaps with generalized epilepsy with febrile seizures plus type-3. The first of these, R43Q, abolishes benzodiazepine potentiation of GABA induced currents. The second associated mutation, C588T has not been further characterized. # Diagnosis Diagnosis is made upon history of absence seizures during early childhood and the observation of ~3Hz spike-and-wave discharges on an EEG. # Treatment/Management See the corresponding section in the main epilepsy article. The primary goal of treatment of childhood absence epilepsy is to prevent accidental injuries that may occur during seizures. For those with frequent seizures the goal of treatment includes preventing the seizures from interfering with learning at school and other activities of daily life. The goal of treatment with medications for absence seizures is to accomplish the goals above, by eliminating or reducing the frequency of the absence seizures, without causing side-effects more serious than the epilepsy itself. Certain anticonvulsant drugs are used to minimize the number of seizures. Absence seizures appear to respond well to valproic acid (trade name: Depakote), ethosuximide (trade name: Zarontin), and lamotrigine (trade name: Lamictal). Each of these medications has potential side effects, some of them serious. While the most serious side effects are uncommon, a better understanding of the risks and benefits of each of these medications would benefit many parents and guardians who must consent to treatment for their children. For childhood absence epilepsy, there is insufficient evidence to know which, if any, of the available medications is best, i.e., having the best combination of safety and efficacy. Nor is it known how long medication must be continued before a trial off medication should be conducted to determine if the individual has outgrown the absence seizures, as children so often do. To date, there have been no published results of any large, double-blind, placebo-controlled studies comparing the efficacy and safety of these or any other medications for absence seizures. The U.S. government is currently sponsoring such a study. The purpose of this study is to determine the best initial treatment for childhood absence epilepsy from among valproic acid, ethosuximide and lamotrigine. In addition, the researchers hope to develop methods that may be used in the future to help choose the best medicine for each child diagnosed with absence seizures. The 5-year study began in 2004, and is expected to involve more than 400 children. Also included in the study will be pharmacokinetics and pharmacogenetics research. Pharmacokinetics is the study of how the body absorbs, distributes, metabolizes, and excretes drugs. Pharmacogenetics is the study of genetic determinants of the response to drugs. Knowledge gained from this study may lead to individualized treatment for children with absence seizures. # Epidemiology Childhood absence epilepsy is a fairly common disorder with a prevalence of 1 in 1000 people. Few of these people will likely have mutations in CACNA1H or GABRG2 as the prevalence of those in the studies presented is 10% or less.

Fregoli delusion # Overview The Fregoli delusion or Fregoli syndrome is a rare disorder in which a person holds a delusional belief that different people are in fact a single person who changes appearance or is in disguise. The syndrome may be related to a brain lesion and is often of a paranoid nature with the delusional person believing that he or she is being persecuted by the person he or she believes to be in disguise. The condition is named after the Italian actor Leopoldo Fregoli who was renowned for his ability to make quick changes of appearance during his stage act. It was first reported in a paper by P. Courbon and G. Fail in 1927 (Syndrome d’illusion de Frégoli et schizophrénie). They discussed the case study of a 27-year-old woman who believed she was being persecuted by two actors whom she often went to see at the theatre. She believed that these people "pursued her closely, taking the form of people she knows or meets". The Fregoli delusion is classed both as a monothematic delusion, since it only encompasses one delusional topic, and as a delusional misidentification syndrome, a class of delusional beliefs that involves the misidentification of people, places or objects. Like Capgras delusion, it is thought to be related to a breakdown in normal face perception. # Symptoms - Delusions/hallucinations. - Defeciency of visual memory. - Self awareness defeciency. - Executive function defeciency. - Hindrance of cognitive flexibility. - Seizures/epileptogenic symptoms. # Etiology - Levodopa therapy- It is clinically used to treat Parkinson's disease and dopamine-responsive dystonia. Clinical studies have shown that the use of levodopa can lead to visual hallucinations and delusions. In most patients, delusions were more salient than hallucinations. Over prolonged use of levodopa, the delusions almost occupy all of a patient's attention. It has been concluded that delusions related to antiparkinsonian medications are one of the leading causes of Fregoli syndrome. - Traumatic brain injury- Injury to the right frontal and left temporo-parietal areas can cause Fregoli syndrome. It has been seen that significant deficits in executive and memory functions follow shortly after damage in the right frontal or left temporoparietal areas. - Lesion in Fusiform gyrus- Lesions in the right temporal lobe and the fusiform gyrus may contribute to DMSs. MRIs of patients exemplifying Fregoli symptoms have shown parahippocampal and hippocampal damage in the anterior fusiform gyrus, as well as the middle and inferior of the right temporal gyri. The inferior and medial of the right temporal gyri are the storage locations for long-term memory in retrieving information on visual recognition, specifically of faces; thus, damage to these intricate connections could be one of the leading factors in face misidentification disorders. - Abnormal P300- In comparison to normal patients, DMS patients generally exhibit an attenuated amplitude of P300 at many abductions. These patients also exhibit prolonged latencies of P300 at all abductions. These implications suggest that DMSs are accompanied by abnormal WM, specifically affecting the prefrontal cortex (both outside and inside). # Treatment Antipsychotic drugs are the frontrunners in treatment for Fregoli and other DMSs. In addition to antipsychotics, anticonvulsants and antidepressants are also prescribed in some treatment courses.

UCSF Medical Center The UCSF Medical Center is a major research and teaching hospital in San Francisco, California. With campuses located at Parnassus Heights and Mount Zion, UCSF Medical Center is affiliated with the University of California, San Francisco. It has been ranked as the 7th-best overall medical center in the United States by U.S.News & World Report. The following specialties were ranked in the top 10: endocrinology (4); neurology and neurosurgery (5); gynecology (6); urology (8); rheumatology (9); ophthalmology (9). A new 43-acre campus in the Mission Bay neighborhood is expected to eventually host new hospital facilities. # Parnassus The 600-bed Parnassus center serves as the main campus and houses the Langley Porter Psychiatric Institute, The 180-bed UCSF Children's Hospital, extensive research labs, and the main Dental and Nursing buildings. # Mount Zion The Mount Zion hospital has the UCSF Comprehensive Cancer Center, the Women's Health Center, and School of Pharmancy buildings. The UCSF Medical Center is considered one of the top hospitals in the nation, and ranks in the top ten in the US News 2005 survey. The Medical Center conducts research in almost every field of medicine and supports top-notch programs in many specialties including AIDS, cancer, and pediatric research. # External link - Official website

Cooking Cooking is the act of preparing food for eating by the application of heat. It encompasses a vast range of methods, tools and combinations of ingredients to alter the flavor or digestibility of food. It is the general preparation process of selecting, measuring and combining of ingredients in an ordered procedure in an effort to achieve the desired result. Factors affecting the final outcome include the variability of ingredients, ambient conditions, tools, and the skill of the individual doing the actual cooking. The diversity of cooking worldwide is a reflection of the myriad nutritional, aesthetic, agricultural, economic, cultural, social and religious considerations that impact upon it. Applying heat to a food usually, though not always, chemically transforms it, thus changing its flavor, texture, consistency, appearance, and nutritional properties. There is archaeological evidence of roasted foodstuffs, both animal and vegetable, in human (Homo erectus) campsites dating from the earliest known use of fire, some 800,000 years ago. Other methods of cooking that involve the boiling of liquid in a receptacle have been practiced at least since the 10th millennium BC, with the introduction of pottery. # Effects of cooking ## Proteins Edible animal material, including muscle, offal, milk and egg white, contains substantial amounts of protein. Almost all vegetable matter (in particular legumes and seeds) also includes proteins, although generally in smaller amounts. These may also be a source of essential amino acids. When proteins are heated they become de-natured and change texture. In many cases, this causes the structure of the material to become softer or more friable - meat becomes cooked. In some cases, proteins can form more rigid structures, such as the coagulation of albumen in egg whites. The formation of a relatively rigid but flexible matrix from egg white provides an important component of much cake cookery, and also underpins many desserts based on meringue. ## Liquids Cooking often involves water which is frequently present as other liquids, both added in order to immerse the substances being cooked (typically water, stock or wine), and released from the foods themselves. Liquids are so important to cooking that the name of the cooking method used may be based on how the liquid is combined with the food, as in steaming, simmering, boiling, braising and blanching. Heating liquid in an open container results in rapidly increased evaporation, which concentrates the remaining flavor and ingredients - this is a critical component of both stewing and sauce making. ## Fat Fats and oils come from both animal and plant sources. In cooking, fats provide tastes and textures. When used as the principal cooking medium (rather than water), they also allow the cook access to a wide range of cooking temperatures. Common oil-cooking techniques include sauteing, stir-frying, and deep-frying. Commonly used fats and oils include butter; olive oil; vegetable oils such as sunflower oil, corn oil, and safflower oil; animal fats such as lard, schmaltz, and beef fat (both dripping and tallow); and seed oils such as rapeseed oil (Canola or mustard oil), sesame oil, soybean oil, and peanut oil. The inclusion of fats tends to add flavour to cooked food, even though the taste of the oil on its own is often unpleasant. This fact has encouraged the popularity of high fat foods, many of which are classified as junk food. ## Carbohydrates Cooking include simple sugars such as glucose (from table sugar) and fructose (from fruit), and starches from sources such as cereal flour, rice, arrowroot, potato. The interaction of heat and carbohydrate is complex. Long-chain sugars such as starch tend to break down into more simple sugars when cooked, while simple sugars can form syrups. If sugars are heated so that all water of crystallisation is driven off, then caramelisation starts, with the sugar undergoing thermal decomposition with the formation of carbon, and other breakdown products producing caramel. Similarly, the heating of sugars and proteins elicits the Maillard reaction, a basic flavor-enhancing technique. An emulsion of starch with fat or water can, when gently heated, provide thickening to the dish being cooked. In European cooking, a mixture of butter and flour called a roux is used to thicken liquids to make stews or sauces. In Asian cooking, a similar effect is obtained from a mixture of rice or corn starch and water. These techniques rely on the properties of starches to create simpler mucilaginous saccharides during cooking, which causes the familiar thickening of sauces. This thickening will break down, however, under additional heat. # Food safety If heat is used in the preparation of food, this can kill or inactivate potentially harmful organisms including bacteria and viruses. The effect will depend on temperature, cooking time, and technique used. The temperature range from 41°F to 135°F (5°C to 57°C) is the "food danger zone." Between these temperatures bacteria can grow rapidly. Under optimal conditions, E. coli, for example, can double in number every twenty minutes. The food may not appear any different or spoiled but can be harmful to anyone who eats it. Meat, poultry, dairy products, and other prepared food must be kept outside of the "food danger zone" to remain safe to eat. Refrigeration and freezing do not kill bacteria, but only slow their growth. When cooling hot food, it shouldn't be left on the side or in a blast chiller (an appliance used to quickly cool food) for more than 90 minutes. Cutting boards are a potential breeding ground for bacteria, and can be quite hazardous unless safety precautions are taken. Plastic cutting boards are less porous than wood and have conventionally been assumed to be far less likely to harbor bacteria. This has been debated, and some research have shown wooden boards are far better. Washing and sanitizing cutting boards is highly recommended, especially after use with raw meat, poultry, or seafood. Hot water and soap followed by a rinse with an antibacterial cleaner (dilute bleach is common in a mixture of 1 tablespoon per gallon of water, as at that dilution it is considered food safe, though some professionals choose not to use this method because they believe it could taint some foods), or a trip through a dishwasher with a "sanitize" cycle, are effective methods for reducing the risk of illness due to contaminated cooking implements. # Science of cooking The application of scientific knowledge to cooking and gastronomy has become known as molecular gastronomy. This is a subdiscipline of food science. Important contributions have been made by scientists, chefs and authors such as Herve This (chemist), Nicholas Kurti (physicist), Peter Barham (physicist), Harold McGee (author), Shirley Corriher (biochemist, author), Heston Blumenthal (chef), Ferran Adria (chef), Robert Wolke (chemist, author) and Pierre Gagnaire (chef). ## The culinary triangle The culinary triangle is a concept thought up by Claude Lévi-Strauss involving three types of cooking; these are boiling, roasting, and smoking, usually done to meats. The boiling of meat is looked at as a cultural way of cooking because it uses a receptacle to hold water, therefore it is not completely natural. It is also the most preferred way to cook due to the fact that neither any of the meat or its juices are lost. In most cultures, this form of cooking is most represented by women and is served domestically to small closed groups, such as families. Roasting of meat is a natural way of cooking because it uses no receptacle. It is done by directly exposing the meat to the fire. It is most commonly offered to guests and is associated with men in many cultures. As opposed to boiling, meat can lose some parts, thus it is also associated with destruction and loss. Smoking meat is also a natural way of cooking. It is also done without a receptacle and in the same way as roasting. It is a slower method of roasting, however, which makes it somewhat like boiling.

Autonomic nervous system # Overview The autonomic nervous system (ANS) (or visceral nervous system) is the part of the peripheral nervous system that acts as a control system, maintaining homeostasis in the body. These maintenance activities are primarily performed without conscious control or sensation. The ANS has far reaching effects, including: heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils, micturition (the discharge of urine), and sexual arousal. Whereas most of its actions are involuntary, some ANS functions work in tandem with the conscious mind, such as breathing. Its main components are its sensory system, motor system (comprised of the parasympathetic nervous system and sympathetic nervous system), and the enteric nervous system. The ANS is a classical term, widely used throughout the scientific and medical community. Its most useful definition could be: the sensory and motor neurons that innervate the viscera. These neurons form reflex arcs that pass through the lower brainstem or medulla oblongata. This explains that when the central nervous system (CNS) is damaged experimentally or by accident above that level, a vegetative life is still possible, whereby cardiovascular, digestive and respiratory functions are adequately regulated. # Anatomy The reflex arcs of the ANS comprise a sensory (or afferent) arm, and a motor (or efferent, or effector) arm. The latter alone is represented on the figure. ## Sensory neurons The sensory arm is made of “primary visceral sensory neurons” found in the peripheral nervous system (PNS), in “cranial sensory ganglia”: the geniculate, petrosal and nodose ganglia, appended respectively to cranial nerves VII, IX and X. These sensory neurons monitor the levels of carbon dioxide, oxygen and sugar in the blood, arterial pressure and the chemical composition of the stomach and gut content. (They also convey the sense of taste, a conscious perception). Blood oxygen and carbon dioxide are in fact directly sensed by the carotid body, a small collection of chemosensors at the bifurcation of the carotid artery, innervated by the petrosal (IXth) ganglion. Primary sensory neurons project (synapse) onto “second order” or relay visceral sensory neurons located in the medulla oblongata, forming the nucleus of the solitary tract (nTS), that integrates all visceral information. The nTS also receives input from a nearby chemosensory center, the area postrema, that detects toxins in the blood and the cerebrospinal fluid and is essential for chemically induced vomiting and conditional taste aversion (the memory that ensures that an animal which has been poisoned by a food never touches it again). All these visceral sensory informations constantly and unconsciously modulate the activity of the motor neurons of the ANS ## Motor neurons Motor neurons of the ANS are also located in ganglia of the PNS, called “autonomic ganglia”. They belong to three categories with different effects on their target organs (see below “Function”): sympathetic, parasympathetic and enteric. Sympathetic ganglia are located in two sympathetic chains close to the spinal cord: the prevertebral and pre-aortic chains. Parasympathetic ganglia, in contrast, are located in close proximity to the target organ: the submandibular ganglion close to salivatory glands, paracardiac ganglia close to the heart etc… Enteric ganglia, which as their name implies innervate the digestive tube, are located inside its walls and collectively contain as many neurons as the entire spinal cord, including local sensory neurons, motor neurons and interneurons. It is the only truly autonomous part of the ANS and the digestive tube can function surprisingly well even in isolation. For that reason the enteric nervous system has been called “the second brain”. The activity of autonomic ganglionic neurons is modulated by “preganglionic neurons” (also called improperly but classically "visceral motoneurons") located in the central nervous system. Preganglionc sympathetic neurons are in the spinal cord, at thoraco-lumbar levels. Preganglionic parasympathetic neurons are in the medulla oblongata (forming visceral motor nuclei: the dorsal motor nucleus of the vagus nerve (dmnX), the nucleus ambiguus, and salivatory nuclei) and in the sacral spinal cord. Enteric neurons are also modulated by input from the CNS, from preganglionic neurons located, like parasympathetic ones, in the medulla oblongata (in the dmnX). The feedback from the sensory to the motor arm of visceral reflex pathways is provided by direct or indirect connections between the nucleus of the solitary tract and visceral motoneurons. # Function Sympathetic and parasympathetic divisions typically function in opposition to each other. But this opposition is better termed complementary in nature rather than antagonistic. For an analogy, one may think of the sympathetic division as the accelerator and the parasympathetic division as the brake. The sympathetic division typically functions in actions requiring quick responses. The parasympathetic division functions with actions that do not require immediate reaction. Consider sympathetic as "fight or flight" and parasympathetic as "rest and digest". However, many instances of sympathetic and parasympathetic activity cannot be ascribed to "fight" or "rest" situations. For example, standing up from a reclining or sitting position would entail an unsustainable drop in blood pressure if not for a compensatory increase in the arterial sympathetic tonus. Another example is the constant, second to second modulation of heart rate by sympathetic and parasympathetic influences, as a function of the respiratory cycles. More generally, these two systems should be seen as permanently modulating vital functions, in usually antagonistic fashion, to achieve homeostasis. Some typical actions of the sympathetic and parasympathetic systems are listed below: ## Sympathetic nervous system Promotes a "fight or flight" response, corresponds with arousal and energy generation, inhibits digestion: - Diverts blood flow away from the gastro-intestinal (GI) tract and skin via vasoconstriction. - Blood flow to skeletal muscles, the lung is not only maintained, but enhanced (by as much as 1200%, in the case of skeletal muscles). - Dilates bronchioles of the lung, which allows for greater alveolar oxygen exchange. - Increases heart rate and the contractility of cardiac cells (myocytes), thereby providing a mechanism for the enhanced blood flow to skeletal muscles. - Dilates pupils and relaxes the lens, allowing more light to enter the eye. ## Parasympathetic nervous system Promotes a *rest and digest" response; promotes calming of the nerves and return to regular function, enhances digestion. - Dilates blood vessels leading to the GI tract, increasing blood flow. This is important following the consumption of food, due to the greater metabolic demands placed on the body by the gut. - The parasympathetic nervous system can also constrict the bronchiolar diameter when the need for oxygen has diminished. - During accommodation, the parasympathetic nervous system causes constriction of the pupil and lens. - The parasympathetic nervous system stimulates salivary gland secretion, and accelerates peristalsis, so, in keeping with the rest and digest functions, appropriate PNS activity mediates digestion of food and indirectly, the absorption of nutrients. - Is also involved in erection of genitals, via the pelvic splanchnic nerves 2–4. # Neurotransmitters and pharmacology At the effector organs, sympathetic ganglionic neurons release noradrenaline (norepinephrine), along with other cotransmittors such as ATP, to act on adrenergic receptors, with the exception of the sweat glands and the adrenal medulla: - acetycholine is the preganglionic neurotransmitter for both divisions of the ANS, as well as the postganglionic neurotransmitter of parasympathetic neurons. Nerves that release acetylcholine are said to be cholinergic. In the parasympathetic system, ganglionic neurons use acetylcholine as a neurotransmitter, to stimulate muscarinic receptors. - At the adrenal cortex, there is no postsynaptic neuron. Instead the presynaptic neuron releases acetylcholine to act on nicotinic receptors. - Stimulation of the adrenal medulla releases adrenaline (epinephrine) into the bloodstream which will act on adrenoceptors, producing a widespread increase in sympathetic activity. The following table reviews the actions of these neurotransmitters as a function of their receptors. ## circulatory system ### Heart ### Blood vessels ### Other ## respiratory system The bronchioles have no sympathetic innervation, but are instead affected by circulating adrenaline ## nervous system ## digestive system ## endocrine system ## urinary system ## reproductive system ## integument

Ejaculatory duct obstruction # Overview - Ejaculatory duct obstruction may be either congenital or acquired. Because the hypothalamic pituitary gonadal axis is intact, serum hormone levels are normal. # Classification Ejaculatory duct obstruction may be complete or partial. - Complete form: patients have a total absence of sperm in the ejaculate - Partial form: sperm are found in the semen but exhibit reduced numbers, reduced motility, on both. Ejaculate volume is consistently decreased. # Causes - Causes include idiopathic, transurethnal endoscopic procedures, urethral catheterization, and urethritis. # Diagnosis Diagnosis of ejaculatory duct obstruction is suggested by the presence of a cyst posterior to the prostatic urethra, with on without dilatation of the seminal vesicles. MR images demonstrate left ejaculatory duct obstruction

Progressive nonfluent aphasia # Overview Progressive nonfluent aphasia is one of three clinical syndromes associated with frontotemporal lobar degeneration. # Clinical Features The main clinical features are progressive difficulties with speech production. There can be problems in different parts of the speech production system, hence patients can present with articulatory breakdown (hesitant, effortful speech or speech 'apraxia'), agrammatism (difficulties with syntax e.g. use of the wrong tense or word order), anomia or phonemic breakdown (difficulties with sounds). However, it is rare for patients to have just one of these problems and most people will present with more than one problem. Features therefore include: - Hesitant, effortful speech - Stutter (including return of a childhood stutter) - Anomia - Phonemic paraphasias (sound errors in speech e.g. 'gat' for 'cat') - Agrammatism - As the disease develops speech quantity decreases and many patients will become mute. Cognitive domains other than language are rarely affected early on. However, as the disease progresses other domains can be affected. Problems with writing, reading and speech comprehension can occur as can behavioural features similar to frontotemporal dementia. # Nosology There is some confusion in the terminology used by different neurologists. Mesulam's original description in 1982 of progressive language problems caused by neurodegenerative disease (which he called primary progressive aphasia - PPA) included patients with both progressive non-fluent aphasia (PNFA) and semantic dementia (SD). The Neary criteria for PNFA and SD are therefore different to the Mesulam criteria for PPA. This is further confused by some doctors using the term primary progressive aphasia to mean patients with progressive non-fluent aphasia only. (See Knibb and Hodges recent paper for a good discussion of this ongoing problem - "Semantic dementia and primary progressive aphasia: a problem of categorization?" Alzheimer Dis Assoc Disord. 2005 Oct-Dec;19 Suppl 1:S7-14.) # Imaging Imaging studies have shown differing results which probably represents the heterogeneity of language problems than can occur in PNFA. However, classically atrophy of left perisylvian areas is seen. # Management There is no curative treatment for this condition. Supportive management is helpful.

Meropenem warnings # Warnings ## Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with β-lactams. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another β-lactam. before initiating therapy with merrem i.v., careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens. If an allergic reaction to merrem i.v. occurs, discontinue the drug immediately. serious anaphylactic reactions require immediate emergency treatment with epinephrine,oxygen, intravenous steroids, and airway management, including intubation. Other therapy may also be administered as indicated. ## Seizure Potential Seizures and other CNS adverse experiences have been reported during treatment with MERREM I.V.. ## Interaction with Valproic Acid Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction. The concomitant use of meropenem and valproic acid or divalproex sodium is generally not recommended. Antibacterials other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of MERREM I.V. is necessary, supplemental anti-convulsant therapy should be considered. ## Clostridium difficile–Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including MERREM I.V., and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. ## Development of Drug-Resistant Bacteria Prescribing MERREM I.V. in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. ## Overgrowth of Nonsusceptible Organisms As with other broad-spectrum antibiotics, prolonged use of meropenem may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient is essential. If superinfection does occur during therapy, appropriate measures should be taken. ## Laboratory Tests While MERREM I.V. possesses the characteristic low toxicity of the beta-lactam group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. ## Patients with Renal Impairment In patients with renal impairment, thrombocytopenia has been observed but no clinical bleeding reported. ## Dialysis There is inadequate information regarding the use of MERREM I.V. in patients on hemodialysis or peritoneal dialysis. ## Potential for Neuromotor Impairment Patients receiving MERREM I.V. on an outpatient basis may develop adverse events such as seizures, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment. Until it is reasonably well established that MERREM I.V. is well tolerated, patients should not operate machinery or motorized vehicles.

Topiramate drug interactions For patient information about topiramate, click here. # Drug Interactions In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. In vitro studies indicate that topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. Drug interactions with some antiepileptic drugs, CNS depressants and oral contraceptives are described here. For other drug interactions, please refer to Clinical Pharmacology (12.3). ## Antiepileptic Drugs Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. Concomitant administration of phenytoin or carbamazepine with topiramate decreased plasma concentrations of topiramate by 48% and 40%, respectively when compared to topiramate given alone [see Clinical Pharmacology. Concomitant administration of valproic acid and topiramate. has been associated with hyperammonemia with and without encephalopathy. Concomitant administration of topiramate with valproic acid has also been associated with hypothermia (with and without hyperammonemia) in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported . The effects of these interactions on mean plasma AUCs are summarized in the Table 12. In Table 12, the second column (AED concentration) describes what happens to the concentration of the AED listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the coadministration of a drug listed in the first column modifies the concentration of topiramate in experimental settings when topiramate was given alone. In addition to the pharmacokinetic interaction described in the above table, concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy and hypothermia. ### Concomitant administration of valproic acid and topiramate Has been associated with hyperammonemia with and without encephalopathy. Concomitant administration of topiramate with valproic acid has also been associated with hypothermia (with and without hyperammonemia) in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported . ## CNS Depressants Concomitant administration of topiramate and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, topiramate should be used with extreme caution if used in combination with alcohol and other CNS depressants. ## Oral Contraceptives Exposure to ethinyl estradiol was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when topiramate was given as adjunctive therapy in patients taking valproic acid. However, norethindrone exposure was not significantly affected. In another pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate, given in the absence of other medications at doses of 50 to 200 mg/day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with topiramate. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding . In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate, given in the absence of other medications at doses of 50 to 200 mg/day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, topiramate (50 mg/day to 800 mg/day) did not significantly affect exposure to NET. Although there was a dose-dependent decrease in EE exposure for doses between 200 and 800 mg/day, there was no significant dose-dependent change in EE exposure for doses of 50 to 200 mg/day. The clinical significance of the changes observed is not known. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with topiramate. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding ## Digoxin In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established. ## Hydrochlorothiazide A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg q 24 h) and topiramate (96 mg q 12 h) when administered alone and concomitantly. The results of this study indicate that topiramate Cmax increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate therapy may require an adjustment of the topiramate dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination. ## Metformin Topiramate treatment can frequently cause metabolic acidosis, a condition for which the use of metformin is contraindicated Topiramate treatment can frequently cause metabolic acidosis, a condition for which the use of metformin is contraindicated. A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hr) and topiramate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hr) were given simultaneously. The results of this study indicated that the mean metformin Cmax and AUC0-12h increased by 17% and 25%, respectively, when topiramate was added. Topiramate did not affect metformin tmax. The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear . ## Pioglitazone A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUC⛬,ss of pioglitazone with no alteration in Cmax,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in Cmax,ss and AUC⛬,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in Cmax,ss and AUC⛬,ss of the active keto-metabolite. The clinical significance of these findings is not known. When topiramate is added to pioglitazone therapy or pioglitazone is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state. ## Glyburide A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 22% decrease in Cmax and a 25% reduction in AUC24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4-trans-hydroxy­glyburide (M1) and 3-cis-hydroxyglyburide (M2), was also reduced by 13% and 15%, and Cmax was reduced by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. ## Lithium In patients, lithium levels were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for Cmax and 26% for AUC) following topiramate doses of up to 600 mg/day. Lithium levels should be monitored when coadministered with high-dose topiramate [see Clinical Pharmacology. In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for Cmax and 26% for AUC) following topiramate doses up to 600 mg/day. Lithium levels should be monitored when coadministered with high-dose topiramate. ## Haloperidol The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females). ## Amitriptyline There was a 12% increase in AUC and Cmax for amitriptyline (25 mg per day) in 18 normal subjects (9 males, 9 females) receiving 200 mg/day of topiramate. Some subjects may experience a large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patient’s clinical response and not on the basis of plasma levels. ## Sumatriptan Multiple dosing of topiramate (100 mg every 12 hrs) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg). ## Risperidone When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg/day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg/day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Coadministration of topiramate 400 mg/day with risperidone resulted in a 14% increase in Cmax and a 12% increase in AUC12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance. ## Propranolol Multiple dosing of topiramate (200 mg/day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg/day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate, at a dose of 200 mg/day of topiramate. ## Dihydroergotamine Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study. ## Diltiazem Coadministration of diltiazem (240 mg Cardizem CD®) with topiramate (150 mg/day) resulted in a 10% decrease in Cmax and a 25% decrease in diltiazem AUC, a 27% decrease in Cmax and an 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Coadministration of topiramate with diltiazem resulted in a 16% increase in Cmax and a 19% increase in AUC12 of topiramate. ## Venlafaxine Multiple dosing of topiramate (150 mg/day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg Effexor XR®) did not affect the pharmacokinetics of topiramate. ## Other Carbonic Anhydrase Inhibitors Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if topiramate is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis. - As topiramate inhibits carbonic anhydrase, the concomitant use of other inhibitors of carbonic anhydrase (e.g. acetazolamide) may lead to an increased risk of renal stones. - Enzyme inductors (e.g. carbamazepine) : The elimination of topiramate may be increased, possibly requiring dose escalations of topiramate. - Phenytoin : Topiramate may increase the plasma-levels of phenytoin. - Topiramate itself is a weak inhibitor of CYP2C19 and induces CYP 3A4. Under topiramate a decrease of plasma-levels of estrogens (e.g. 'the pill') and digoxin have been noted. - Alcohol may cause increased sedation or drowsiness, and increase the risk of having a seizure. - As listed in the 06/29/2005 label posted at the Drugs@FDA website page 14,'conditions or therapies that predispose to acidosis may be additive to the bicarbonate lowering effects of Topiramate'. Absent from this label is any direct discussion of narcotic (drugs known to promote respiratory acidosis) interactions. This discussion on page 14 is under the topic of Metabolic Acidosis, and is not repeated under the topic of interactions. - Oral contraceptives: Decreased contraceptive efficacy and increased breakthrough bleeding should be considered, especially at doses greater than 200 mg/day . - Metformin is contraindicated with metabolic acidosis, an effect of topiramate. - Lithium levels should be monitored when coadministered with high-dose topiramate. - Other carbonic anhydrase inhibitors: Monitor the patient for the appearance or worsening of metabolic acidosis. ## Drug/Laboratory Tests Interactions There are no known interactions of topiramate with commonly used laboratory tests.

Sodium tetradecyl sulfate # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Sodium tetradecyl sulfate is a sclerosing Agent that is FDA approved for the treatment of small uncomplicated varicose veins of the lower extremities. Common adverse reactions include Local reactions consisting of pain, urticaria or ulceration, Allergic reactions. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Sotradecol (sodium tetradecyl sulfate injection) is indicated in the treatment of small uncomplicated varicose veins of the lower extremities that show simple dilation with competent valves. The benefit-to-risk ratio should be considered in selected patients who are great surgical risks. ### Dosage - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if precipitated or discolored. - Sotradecol (sodium tetradecyl sulfate injection) is for intravenous use only. The strength of solution required depends on the size and degree of varicosity. In general, the 1% solution will be found most useful with the 3% solution preferred for larger varicosities. The dosage should be kept small, using 0.5 mL to 2 mL (preferably 1 mL maximum) for each injection, and the maximum single treatment should not exceed 10 mL. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sodium tetradecyl sulfate in adult patients. ### Non–Guideline-Supported Use - Esophageal varices - Hemangioma # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Sodium tetradecyl sulfate in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sodium tetradecyl sulfate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sodium tetradecyl sulfate in pediatric patients. # Contraindications - Sotradecol (sodium tetradecyl sulfate injection) is contraindicated in previous hypersensitivity reactions to the drug; in acute superficial thrombophlebitis; valvular or deep vein incompetence; huge superficial veins with wide open communications to deeper veins; phlebitis migrans; acute cellulitis; allergic conditions; acute infections; varicosities caused by abdominal and pelvic tumors unless the tumor has been removed; bedridden patients; such uncontrolled systemic diseases as diabetes, toxic hyperthyroidism, tuberculosis, asthma, neoplasm, sepsis, blood dyscrasias and acute respiratory or skin diseases. # Warnings - Sotradecol (sodium tetradecyl sulfate injection) should only be administered by a healthcare professional experienced in venous anatomy and the diagnosis and treatment of conditions affecting the venous system and familiar with proper injection technique. Severe adverse local effects, including tissue necrosis, may occur following extravasation; therefore, extreme care in intravenous needle placement and using the minimal effective volume at each injection site are important. - Emergency resuscitation equipment should be immediately available. Allergic reactions, including fatal anaphylaxis, have been reported. As a precaution against anaphylactic shock, it is recommended that 0.5 mL of Sotradecol be injected into a varicosity, followed by observation of the patient for several hours before administration of a second or larger dose. The possibility of an anaphylactic reaction should be kept in mind, and the physician should be prepared to treat it appropriately. - Because of the danger of thrombosis extension into the deep venous system, thorough preinjection evaluation for valvular competency should be carried out and slow injections with a small amount (not over 2 mL) of the preparation should be injected into the varicosity. Deep venous patency must be determined by noninvasive testing such as duplex ultrasound. Venous sclerotherapy should not be undertaken if tests such as Trendelenberg and Perthes, and angiography show significant valvular or deep venous incompetence. - The development of deep vein thrombosis and pulmonary embolism have been reported following sclerotherapy treatment of superficial varicosities. Patients should have post-treatment follow-up of sufficient duration to assess for the development of deep vein thrombosis. Embolism may occur as long as four weeks after injection of sodium tetradecyl sulfate. Adequate post-treatment compression may decrease the incidence of deep vein thrombosis. ### Precautions - Extreme caution must be exercised in the presence of underlying arterial disease such as marked peripheral arteriosclerosis or thromboangiitis obliterans (Buerger's Disease). # Adverse Reactions ## Clinical Trials Experience - Local reactions consisting of pain, urticaria or ulceration may occur at the site of injection. A permanent discoloration may remain along the path of the sclerosed vein segment. Sloughing and necrosis of tissue may occur following extravasation of the drug. - Allergic reactions such as hives, asthma, hay fever and anaphylactic shock have been reported. Mild systemic reactions that have been reported include headache, nausea and vomiting. - At least six deaths have been reported with the use of Sotradecol. Four cases of anaphylactic shock leading to death have been reported in patients who received Sotradecol. One of these four patients reported a history of asthma, a contraindication to the administration of Sotradecol. - One death has been reported in a patient who received Sotradecol and who had been receiving an antiovulatory agent. Another death (fatal pulmonary embolism) has been reported in a 36-year-old female treated with sodium tetradecyl acetate and who was not taking oral contraceptives. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Sodium tetradecyl sulfate in the drug label. # Drug Interactions - No well-controlled studies have been performed on patients taking antiovulatory agents. The physician must use judgment and evaluate any patient taking antiovulatory drugs prior to initiating treatment with Sotradecol. - Heparin should not be included in the same syringe as Sotradecol, since the two are incompatible. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Animal reproduction studies have not been conducted with Sotradecol. It is also not known whether Sotradecol can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sotradecol should be given to a pregnant woman only if clearly needed and the benefits outweigh the risks. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sodium tetradecyl sulfate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Sodium tetradecyl sulfate during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sotradecol is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use There is no FDA guidance on the use of Sodium tetradecyl sulfate with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Sodium tetradecyl sulfate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sodium tetradecyl sulfate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Sodium tetradecyl sulfate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Sodium tetradecyl sulfate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Sodium tetradecyl sulfate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Sodium tetradecyl sulfate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Sodium tetradecyl sulfate in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Sodium tetradecyl sulfate in the drug label. # Overdosage There is limited information regarding Overdose of Sodium tetradecyl sulfate in the drug label. # Pharmacology ## Mechanism of Action - Sotradecol (sodium tetradecyl sulfate injection) is a sclerosing agent. Intravenous injection causes intima inflammation and thrombus formation. This usually occludes the injected vein. Subsequent formation of fibrous tissue results in partial or complete vein obliteration that may or may not be permanent. ## Structure - Sodium tetradecyl sulfate is an anionic surfactant which occurs as a white, waxy solid. The structural formula is as follows: - Sotradecol (sodium tetradecyl sulfate injection) is a sterile nonpyrogenic solution for intravenous use as a sclerosing agent. - 1% 20 mg/2 mL (10 mg/mL): Each mL contains sodium tetradecyl sulfate 10 mg, benzyl alcohol 0.02 mL and dibasic sodium phosphate, anhydrous 4.0 mg in Water for Injection. pH 7.9; monobasic sodium phosphate and/or sodium hydroxide added, if needed, for pH adjustment. - 3% 60 mg/2 mL (30 mg/mL): Each mL contains sodium tetradecyl sulfate 30 mg, benzyl alcohol 0.02 mL and dibasic sodium phosphate, anhydrous 9.0 mg in Water for Injection. pH 7.9; monobasic sodium phosphate and/or sodium hydroxide added, if needed, for pH adjustment. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Sodium tetradecyl sulfate in the drug label. ## Pharmacokinetics - Sotradecol (sodium tetradecyl sulfate injection) is a sclerosing agent. Intravenous injection causes intima inflammation and thrombus formation. This usually occludes the injected vein. Subsequent formation of fibrous tissue results in partial or complete vein obliteration that may or may not be permanent. ## Nonclinical Toxicology - When tested in the L5178YTK +/- mouse lymphoma assay, sodium tetradecyl sulfate did not induce a dose-related increase in the frequency of thymidine kinase-deficient mutants and, therefore, was judged to be nonmutagenic in this system. However, no long-term animal carcinogenicity studies with sodium tetradecyl sulfate have been performed. - The intravenous LD50 of sodium tetradecyl sulfate in mice was reported to be 90 ± 5 mg/kg. - In the rat, the acute intravenous LD50 of sodium tetradecyl sulfate was estimated to be between 72 mg/kg and 108 mg/kg. - Purified sodium tetradecyl sulfate was found to have an LD50 of 2 g/kg when administered orally by stomach tube as a 25% aqueous solution to rats. In rats given 0.15 g/kg in drinking water for 30 days, no appreciable toxicity was seen, although some growth inhibition was discernible. # Clinical Studies There is limited information regarding Clinical Studies of Sodium tetradecyl sulfate in the drug label. # How Supplied - Sotradecol (sodium tetradecyl sulfate injection) ## Storage - Store at 20° to 25°C (68° to 77°F). # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL - 10 MG/ML CARTON LABEL Sotradecol® 1% (SODIUM TETRADECYL SULFATE INJECTION) 20 mg/2 mL (10 mg/mL) FOR INTRAVENOUS USE ONLY Rx only Distributed by: AngioDynamics, Inc. Queensbury, NY 12804 Manufactured by: Mylan Institutional Galway, Ireland Each mL contains: Sodium tetradecyl sulfate 10 mg, benzyl alcohol 0.02 mL and dibasic sodium phosphate, anhydrous 4.0 mg in Water for Injection. pH 7.9; monobasic sodium phosphate and/or sodium hydroxide added, if needed, for pH adjustment. WARNING: Do not use if precipitated. USUAL DOSAGE: See accompanying prescribing information. Store at 20° to 25°C (68° to 77°F). 0319C102 ### PRINCIPAL DISPLAY PANEL - 30 MG/ML CARTON LABEL 5 x 2 mL Vials NDC 65974-163-02 Sotradecol® 3% (SODIUM TETRADECYL SULFATE INJECTION) 60 mg/2 mL (30 mg/mL) FOR INTRAVENOUS USE ONLY Rx only Distributed by: AngioDynamics, Inc. Queensbury, NY 12804 Manufactured by: Mylan Institutional Galway, Ireland Each mL contains: Sodium tetradecyl sulfate 30 mg, benzyl alcohol 0.02 mL and dibasic sodium phosphate, anhydrous 9.0 mg in Water for Injection. pH 7.9; monobasic sodium phosphate and/or sodium hydroxide added, if needed, for pH adjustment. WARNING: Do not use if precipitated. USUAL DOSAGE: See accompanying prescribing information. Store at 20° to 25°C (68° to 77°F). 0320C102 ### Ingredients and appearance # Patient Counseling Information There is limited information regarding Patient Counseling Information of Sodium tetradecyl sulfate in the drug label. # Precautions with Alcohol - Alcohol-Sodium tetradecyl sulfate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - SOTRADECOL® # Look-Alike Drug Names There is limited information regarding Sodium tetradecyl sulfate Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price

Sulfadiazine indications and usage # Indications and Usage SulfADIAZine tablets USP are indicated in the following conditions: Chancroid Trachoma Inclusion conjunctivitis Nocardiosis Urinary tract infections (primarily pyelonephritis, pyelitis and cystitis) in the absence of obstructive uropathy or foreign bodies, when these infections are caused by susceptible strains of the following organisms: Escherichia coli, Klebsiella species, Enterobacter species, Staphylococcus aureus, Proteus mirabilis and P. vulgaris. Sulfadiazine should be used for urinary tract infections only after use of more soluble sulfonamides has been unsuccessful. Toxoplasmosis encephalitis in patients with and without acquired immunodeficiency syndrome, as adjunctive therapy with pyrimethamine. Malaria due to chloroquine-resistant strains of Plasmodium falciparum, when used as adjunctive therapy. Prophylaxis of meningococcal meningitis when sulfonamide-sensitive group A strains are known to prevail in family groups or larger closed populations (the prophylactic usefulness of sulfonamides when group B or C infections are prevalent is not proved and may be harmful in closed population groups). Meningococcal meningitis, when the organism has been demonstrated to be susceptible. Acute otitis media due to Haemophilusinfluenzae, when used concomitantly with adequate doses of penicillin. Prophylaxis against recurrences of rheumatic fever, as an alternative to penicillin. H. influenzae meningitis, as adjunctive therapy with parental streptomycin. IMPORTANT NOTES In vitro sulfonamide susceptibility tests are not always reliable. The test must be carefully coordinated with bacteriologic and clinical response. When the patient is already taking sulfonamides, follow-up cultures should have aminobenzoic acid added to the culture media. Currently, the increasing frequency of resistant organisms limits the usefulness of antibacterial agents, including the sulfonamides, especially in the treatment of recurrent and complicated urinary tract infections. Wide variation in blood levels may result with identical doses. Blood levels should be measured in patients receiving sulfonamides for serious infections. Free sulfonamide blood levels of 5 mg to 15 mg per 100 mL may be considered therapeutically effective for most infections and blood levels of 12 mg to 15 mg per 100 mL may be considered optimal for serious infections. Twenty mg per 100 mL should be the maximum total sulfonamide level, since adverse reactions occur more frequently above this level.

Fluticasone furoate # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Fluticasone furoate is a anti-allergic agents that is FDA approved for the treatment of symptoms of seasonal and perennial allergic rhinitis in patients aged 2 years and older. Common adverse reactions include candida albicans infection, immunosuppression, hypercorticism and adrenal suppression, reduction in BMD, growth effects in pediatrics, glaucoma and cataracts. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) The recommended starting dosage is 110 mcg once daily administered as 2 sprays (27.5 mcg/spray) in each nostril. When the maximum benefit has been achieved and symptoms have been controlled, reducing the dosage to 55 mcg (1 spray in each nostril) once daily may be effective in maintaining control of allergic rhinitis symptoms. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fluticasone furoate in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Fluticasone furoate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The recommended starting dosage in children is 55 mcg once daily administered as 1 spray (27.5 mcg/spray) in each nostril. Children not adequately responding to 55 mcg may use 110 mcg (2 sprays in each nostril) once daily. Once symptoms have been controlled, dosage reduction to 55 mcg once daily is recommended. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Fluticasone furoate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Fluticasone furoate in pediatric patients. # Contraindications Fluticasone furoate is contraindicated in patients with hypersensitivity to any of its ingredients # Warnings Warnings, precautions and adverse reactions associated with Fluticasone furoate should be taken into account. ### Local Nasal Effects - Epistaxis and Nasal Ulceration. - In clinical trials of 2 to 52 weeks’ duration, epistaxis and nasal ulcerations were observed more frequently and some epistaxis events were more severe in patients treated with VERAMYST Nasal Spray than those who received placebo. Candida Infection - Evidence of localized infection. - Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should not use VERAMYST Nasal Spray until healing has occurred. ### Glaucoma and Cataracts - Nasal and inhaled corticosteroids may result in the development of glaucoma and/or cataracts. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure (IOP), glaucoma, and/or cataracts. - Glaucoma and cataract formation was evaluated with intraocular pressure measurements and slit lamp examinations in 1 controlled 12-month trial in 806 adolescent and adult patients aged 12 years and older and in 1 controlled 12-week trial in 558 children aged 2 to 11 years. The patients had perennial allergic rhinitis and were treated with either VERAMYST Nasal Spray (110 mcg once daily in adult and adolescent patients and 55 or 110 mcg once daily in pediatric patients) or placebo. Intraocular pressure remained within the normal range (<21 mmHg) in ≥98% of the patients in any treatment group in both trials. However, in the 12-month trial in adolescents and adults, 12 patients, all treated with VERAMYST Nasal Spray 110 mcg once daily, had intraocular pressure measurements that increased above normal levels (≥21 mmHg). In the same trial, 7 patients (6 treated with VERAMYST Nasal Spray 110 mcg once daily and 1 patient treated with placebo) had cataracts identified during the trial that were not present at baseline. ### Hypersensitivity Reactions - Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria, may occur after administration of VERAMYST Nasal Spray. Discontinue VERAMYST Nasal Spray if such reactions occur. ### Immunosuppression - Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. - In children or adults who have not had these diseases or have not been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. - The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. - If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. - If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. - If chickenpox or measles develops, treatment with antiviral agents may be considered. - Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract, untreated local or systemic fungal or bacterial infections, systemic viral or parasitic infections, or ocular herpes simplex because of the potential for worsening of these infections. ### Hypothalamic-Pituitary-Adrenal Axis Effects - Hypercorticism and Adrenal Suppression - When intranasal steroids are used at higher-than-recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of VERAMYST Nasal Spray should be discontinued slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy. - The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency. In addition, some patients may experience symptoms of corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, depression. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In those patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, rapid decreases in systemic corticosteroid dosages may cause a severe exacerbation of their symptoms. ### Use of Cytochrome P450 3A4 Inhibitors - Coadministration with ritonavir is not recommended because of the risk of systemic effects secondary to increased exposure to fluticasone furoate. Use caution with the coadministration of VERAMYST Nasal Spray and other potent cytochrome P450 3A4(CYP3A4) inhibitors, such as ketoconazole. ### Effect on Growth - Corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth routinely of pediatric patients receiving VERAMYST Nasal Spray. To minimize the systemic effects of intranasal corticosteroids, including VERAMYST Nasal Spray, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Fluticasone furoate Clinical Trials Experience in the drug label. ## Postmarketing Experience - Systemic and local corticosteroid use may result in the following: - Epistaxis. - Ulceration. - Candida albicans infection. - Impaired wound healing. - Nasal septal perforation. - Cataracts and glaucoma. - Immunosuppression. - Hypothalamic-pituitary-adrenal (HPA) axis effects, including growth reduction # Drug Interactions - Fluticasone furoate is cleared by extensive first-pass metabolism mediated by CYP3A4. In a drug interaction trial of intranasal fluticasone furoate and the CYP3A4 inhibitor ketoconazole given as a 200-mg once-daily dose for 7 days, 6 of 20 subjects receiving fluticasone furoate and ketoconazole had measurable but low levels of fluticasone furoate compared with 1 of 20 receiving fluticasone furoate and placebo. Based on this trial and the low systemic exposure, there was a 5% reduction in 24-hour serum cortisol levels with ketoconazole compared with placebo. The data from this trial should be carefully interpreted because the trial was conducted with ketoconazole 200 mg once daily rather than 400 mg, which is the maximum recommended dosage. Therefore, caution is required with the coadministration of VERAMYST Nasal Spray and ketoconazole or other potent CYP3A4 inhibitors. - Based on data with another glucocorticoid, fluticasone propionate, metabolized by CYP3A4, coadministration of VERAMYST Nasal Spray with the potent CYP3A4 inhibitor ritonavir is not recommended because of the risk of systemic effects secondary to increased exposure to fluticasone furoate. High exposure to corticosteroids increases the potential for systemic side effects, such as cortisol suppression. - Enzyme induction and inhibition data suggest that fluticasone furoate is unlikely to significantly alter the cytochrome P450-mediated metabolism of other compounds at clinically relevant intranasal dosages. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C ### Teratogenic Effects - Pregnancy Category C. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. - There were no teratogenic effects in rats and rabbits at inhaled fluticasone furoate dosages of up to 91 and 8 mcg/kg/day, respectively (approximately 7 and 1 times, respectively, the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). There was also no effect on pre- or post-natal development in rats treated with up to 27 mcg/kg/day by inhalation during gestation and lactation (approximately 2 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). - There are no adequate and well-controlled studies in pregnant women. VERAMYST Nasal Spray should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects - Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fluticasone furoate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Fluticasone furoate during labor and delivery. ### Nursing Mothers - It is not known whether fluticasone furoate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. - Since there are no data from controlled trials on the use of intranasal fluticasone furoate by nursing mothers, caution should be exercised when VERAMYST Nasal Spray is administered to a nursing woman. ### Pediatric Use - Controlled clinical trials with VERAMYST Nasal Spray included 1,224 patients aged 2 to 11 years and 344 adolescent patients aged 12 to 17 years. - The safety and effectiveness of VERAMYST Nasal Spray in children younger than 2 years have not been established. - Controlled clinical trials have shown that intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. - The long-term effects of reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including VERAMYST Nasal Spray, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks/benefits of treatment alternatives. To minimize the systemic effects of intranasal corticosteroids, including VERAMYST Nasal Spray, each patient’s dose should be titrated to the lowest dosage that effectively controls his/her symptoms. - A randomized, double-blind, parallel-group, multicenter, 1-year placebo-controlled clinical growth trial evaluated the effect of 110 mcg of VERAMYST Nasal Spray once daily on growth velocity in 474 prepubescent children (girls aged 5 to 7.5 years and boys aged 5 to 8.5 years) with stadiometry. Mean growth velocity over the 52-week treatment period was lower in the patients receiving VERAMYST Nasal Spray (5.19 cm/year compared with placebo (5.46 cm/year). The mean treatment difference was -0.27 cm/year . ### Geriatic Use - Clinical studies of VERAMYST Nasal Spray did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Fluticasone furoate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Fluticasone furoate with respect to specific racial populations. ### Renal Impairment No dosage adjustment is required in patients with renal impairment ### Hepatic Impairment Use VERAMYST Nasal Spray with caution in patients with severe hepatic impairment ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Fluticasone furoate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Fluticasone furoate in patients who are immunocompromised. # Administration and Monitoring ### Administration Intranasal ### Monitoring There is limited information regarding Fluticasone furoate Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Fluticasone furoate and IV administrations. # Overdosage - Chronic overdosage may result in signs/symptoms of hypercorticism. There are no data on the effects of acute or chronic overdosage with VERAMYST Nasal Spray. Because of low systemic bioavailability and an absence of acute drug-related systemic findings in clinical trials (with dosages of up to 440 mcg/day for 2 weeks ), overdose is unlikely to require any therapy other than observation. - Intranasal administration of up to 2,640 mcg/day (24 times the recommended adult dose) of fluticasone furoate was administered to healthy human volunteers for 3 days. Single- and repeat-dose trials with orally inhaled fluticasone furoate doses of 50 to 4,000 mcg have shown decreased mean serum cortisol at doses of 500 mcg or higher. The oral median lethal dose in mice and rats was >2,000 mg/kg (approximately 74,000 and 147,000 times, respectively, the maximum recommended daily intranasal dose in adults and 52,000 and 105,000 times, respectively, the maximum recommended daily intranasal dose in children, on a mcg/m2 basis). - Acute overdosage with the intranasal dosage form is unlikely since 1 bottle of VERAMYST Nasal Spray contains approximately 3 mg of fluticasone furoate, and the bioavailability of fluticasone furoate is <1% for 2.64 mg/day given intranasally and 1% for 2 mg/day given as an oral solution. # Pharmacology ## Mechanism of Action - Fluticasone furoate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. The precise mechanism through which fluticasone furoate affects rhinitis symptoms is not known. - Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats. - Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown. ## Structure There is limited information regarding Structure of Conjugated Estrogens in the drug label. ## Pharmacodynamics ### Adrenal Function - The effects of VERAMYST Nasal Spray on adrenal function have been evaluated in 4 controlled clinical trials in patients with perennial allergic rhinitis. - Two 6-week clinical trials were designed specifically to assess the effect of VERAMYST Nasal Spray on the HPA axis with assessments of both 24-hour urinary cortisol excretion and serum cortisol levels in domiciled patients. In addition, one 52-week safety trial and one 12-week safety and efficacy trial included assessments of 24-hour urinary cortisol excretion. - Details of the trials and results are described below. In all 4 trials, since serum fluticasone determinations were generally below the limit of quantification, compliance was assured by efficacy assessments. - Clinical Trials Specifically Designed to Assess Hypothalamic-Pituitary-Adrenal Axis Effect: In a 6-week randomized, double-blind, parallel-group trial in adult and adolescent patients aged 12 years and older with perennial allergic rhinitis, VERAMYST Nasal Spray 110 mcg was compared with both placebo nasal spray and prednisone as a positive-control group that received prednisone 10 mg orally once daily for the final 7 days of the treatment period. Adrenal function was assessed by 24-hour urinary cortisol excretion before and after 6 weeks of treatment and by serial serum cortisol levels. Patients were domiciled for collection of 24-hour urinary cortisol. After 6 weeks of treatment, there was a change from baseline in the mean 24-hour urinary cortisol excretion in the group treated with VERAMYST Nasal Spray (n = 43) of -1.16 mcg/day compared with -3.48 mcg/day in the placebo group (n = 42). The difference from placebo in the group treated with VERAMYST Nasal Spray was 2.32 mcg/day (95% CI: -6.76, 11.39). Urinary cortisol data were not available for the positive-control (prednisone) treatment group. For serum cortisol levels, after 6 weeks of treatment there was a change from baseline in the mean (0-24 hours) of -0.38 and 0.08 mcg/dL for the group treated with VERAMYST Nasal Spray (n = 43) and the placebo group (n = 44), respectively, with a difference between the group treated with VERAMYST Nasal Spray and the placebo group of -0.47 mcg/dL (95% CI: -1.31, 0.37). For comparison, in the positive-control (prednisone, n = 12) treatment group, there was a change in mean serum cortisol (0-24 hours) from baseline of -4.49 mcg/dL with a difference between the prednisone and placebo group of -4.57 mcg/dL (95% CI: -5.83, -3.31). - The second 6-week trial conducted in children aged 2 to 11 years was of similar design to the adult trial, including adrenal function assessments, but did not include a prednisone positive-control arm. Patients were treated once daily with VERAMYST Nasal Spray 110 mcg or placebo nasal spray. After 6 weeks of treatment, there was a change in the mean 24-hour urinary cortisol excretion in the group treated with VERAMYST Nasal Spray (n = 43) of 0.49 mcg/day compared with 1.92 mcg/day in the placebo group (n = 41), with a difference between the group treated with VERAMYST Nasal Spray and the placebo group of -1.43 mcg/day (95% CI: -5.21, 2.35). For serum cortisol levels, after 6 weeks, there was a change from baseline in mean (0-24 hours) of -0.34 and -0.23 mcg/dL for the group treated with VERAMYST Nasal Spray (n = 48) and for the placebo group (n = 47), respectively, with a difference between the group treated with VERAMYST Nasal Spray and the placebo group of -0.11 mcg/dL (95% CI: -0.88, 0.66). ### Additional Hypothalamic-Pituitary-Adrenal Axis Assessments - In the 52-week safety trial in adolescents and adults aged 12 years and older with perennial allergic rhinitis, VERAMYST Nasal Spray 110 mcg (n = 605) was compared with placebo nasal spray (n = 201). Adrenal function was assessed by 24-hour urinary cortisol excretion in a subset of patients who received VERAMYST Nasal Spray (n = 370) or placebo (n = 120) before and after 52 weeks of treatment. After 52 weeks of treatment, the mean change from baseline 24-hour urinary cortisol excretion was 5.84 mcg/day in the group treated with VERAMYST Nasal Spray and 3.34 mcg/day in the placebo group. The difference from placebo in mean change from baseline 24-hour urinary cortisol excretion was 2.50 mcg/day (95% CI: -5.49, 10.49). - In the 12-week safety and efficacy trial in children aged 2 to 11 years with perennial allergic rhinitis, VERAMYST Nasal Spray 55 mcg (n = 185) and VERAMYST Nasal Spray 110 mcg (n = 185) were compared with placebo nasal spray (n = 188). Adrenal function was assessed by measurement of 24-hour urinary free cortisol in a subset of patients who were aged 6 to 11 years (103 to 109 patients per group) before and after 12 weeks of treatment. After 12 weeks of treatment, there was a decrease in mean 24-hour urinary cortisol excretion from baseline in the group treated with VERAMYST Nasal Spray 55 mcg (n = 109) of -2.93 mcg/day and in the group treated with VERAMYST Nasal Spray 110 mcg (n = 103) of -2.07 mcg/day compared with an increase in the placebo group (n = 107) of 0.08 mcg/day. The difference from placebo in mean change from baseline in 24-hour urinary cortisol excretion for the group treated with VERAMYST Nasal Spray 55 mcg was -3.01 mcg/day (95% CI: -6.16, 0.13) and -2.14 mcg/day (95% CI: -5.33, 1.04) for the group treated with VERAMYST Nasal Spray 110 mcg. - When the results of the HPA axis assessments described above are taken as a whole, an effect of intranasal fluticasone furoate on adrenal function cannot be ruled out, especially in pediatric patients. ### Cardiac Effects - A QT/QTc trial did not demonstrate an effect of fluticasone furoate administration on the QTc interval. The effect of a single dose of 4,000 mcg of orally inhaled fluticasone furoate on the QTc interval was evaluated over 24 hours in 40 healthy male and female subjects in a placebo-and positive-controlled (a single dose of 400 mg oral moxifloxacin) cross-over trial. The QTcF maximal mean change from baseline following fluticasone furoate was similar to that observed with placebo with a treatment difference of 0.788 msec (90% CI: -1.802, 3.378). In contrast, moxifloxacin given as a 400-mg tablet resulted in prolongation of the QTcF maximal mean change from baseline compared with placebo with a treatment difference of 9.929 msec (90% CI: 7.339, 12.520). While a single dose of fluticasone furoate had no effect on the QTc interval, the effects of fluticasone furoate may not be at steady state following single dose. The effect of fluticasone furoate on the QTc interval following multiple-dose administration is unknown. ## Pharmacokinetics ### Absorption - Following intranasal administration of fluticasone furoate, most of the dose is eventually swallowed and undergoes incomplete absorption and extensive first-pass metabolism in the liver and gut, resulting in negligible systemic exposure. At the highest recommended intranasal dosage of 110 mcg once daily for up to 12 months in adults and up to 12 weeks in children, plasma concentrations of fluticasone furoate are typically not quantifiable despite the use of a sensitive HPLC-MS/MS assay with a lower limit of quantification (LOQ) of 10 pg/mL. However, in a few isolated cases (<0.3%) fluticasone furoate was detected in high concentrations above 500 pg/mL, and in a single case the concentration was as high as 1,430 pg/mL in the 52-week trial. There was no relationship between these concentrations and cortisol levels in these subjects. The reasons for these high concentrations are unknown. - Absolute bioavailability was evaluated in 16 male and female subjects following supratherapeutic dosages of fluticasone furoate (880 mcg given intranasally at 8-hour intervals for 10 doses, or 2,640 mcg/day). The average absolute bioavailability was 0.50% (90% CI: 0.34%, 0.74%). - Due to the low bioavailability by the intranasal route, the majority of the pharmacokinetic data was obtained via other routes of administration. Trials using oral solution and intravenous dosing of radiolabeled drug have demonstrated that at least 30% of fluticasone furoate is absorbed and then rapidly cleared from plasma. Oral bioavailability is on average 1.26%, and the majority of the circulating radioactivity is due to inactive metabolites. ### Distribution - Following intravenous administration, the mean volume of distribution at steady state is 608 L. - Binding of fluticasone furoate to human plasma proteins is greater than 99%. ### Metabolism - In vivo studies have revealed no evidence of cleavage of the furoate moiety to form fluticasone. Fluticasone furoate is cleared (total plasma clearance of 58.7 L/h) from systemic circulation principally by hepatic metabolism via CYP3A4. The principal route of metabolism is hydrolysis of the S-fluoromethyl carbothioate function to form the inactive 17β-carboxylic acid metabolite. ### Elimination - Fluticasone furoate and its metabolites are eliminated primarily in the feces, accounting for approximately 101% and 90% of the orally and intravenously administered dose, respectively. Urinary excretion accounted for approximately 1% and 2% of the orally and intravenously administered dose, respectively. The elimination phase half-life averaged 15.1 hours following intravenous administration. ### Population Pharmacokinetics - Fluticasone furoate is typically not quantifiable in plasma following intranasal dosing of 110 mcg once daily with the exception of isolated cases of very high plasma levels (see Absorption). Overall, quantifiable levels (>10 pg/mL) were observed in <31% of patients aged 12 years and older and in <16% of children (aged 2 to 11 years) following intranasal dosing of 110 mcg once daily and in <7% of children following intranasal dosing of 55 mcg once daily. There was no evidence to suggest that the presence or absence of detectable levels of fluticasone furoate was related to gender, age, or race. ### Hepatic Impairment - Reduced liver function may affect the elimination of corticosteroids. Since fluticasone furoate undergoes extensive first-pass metabolism by the hepatic CYP3A4, the pharmacokinetics of fluticasone furoate may be altered in patients with hepatic impairment. A trial of a single 400-mcg dose of orally inhaled fluticasone furoate in patients with moderate hepatic impairment (Child-Pugh Class B) resulted in increased Cmax (42%) and AUC(0-∞) (172%), resulting in an approximately 20% reduction in serum cortisol level in patients with hepatic impairment compared with healthy subjects. The systemic exposure would be expected to be higher than that observed had the trial been conducted after multiple doses and/or in patients with severe hepatic impairment. Therefore, use VERAMYST Nasal Spray with caution in patients with severe hepatic impairment. ### Renal Impairment - Fluticasone furoate is not detectable in urine from healthy subjects following intranasal dosing. Less than 1% of dose-related material is excreted in urine. No dosage adjustment is required in patients with renal impairment. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Fluticasone furoate produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at doses of up to 9 and 19 mcg/kg/day, respectively (less than the maximum recommended daily intranasal dose in adults and children on a mcg/m2 basis). - Fluticasone furoate did not induce gene mutation in bacteria or chromosomal damage in a mammalian cell mutation test in mouse lymphoma L5178Y cells in vitro. There was also no evidence of genotoxicity in the in vivo micronucleus test in rats. - No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at inhaled fluticasone furoate doses of up to 24 and 91 mcg/kg/day, respectively (approximately 2 and 7 times, respectively, the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). # Clinical Studies ### Adult and Adolescent Patients Aged 12 Years and Older - The efficacy and safety of VERAMYST Nasal Spray was evaluated in 5 randomized, double-blind, parallel-group, multicenter, placebo-controlled clinical trials of 2 to 4 weeks’ duration in adult and adolescent patients aged 12 years and older with symptoms of seasonal or perennial allergic rhinitis. The 5 clinical trials included one 2-week dose-ranging trial in patients with seasonal allergic rhinitis, three 2-week confirmatory efficacy trials in patients with seasonal allergic rhinitis, and one 4-week efficacy trial in patients with perennial allergic rhinitis. These trials included 1,829 patients (697 males and 1,132 females). About 75% of patients were Caucasian, and the mean age was 36 years. Of these patients, 722 received VERAMYST Nasal Spray 110 mcg once daily administered as 2 sprays in each nostril. - Assessment of efficacy was based on total nasal symptom score (TNSS). TNSS is calculated as the sum of the patients’ scoring of the 4 individual nasal symptoms (rhinorrhea, nasal congestion, sneezing, and nasal itching) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) as reflective(rTNSS) or instantaneous (iTNSS). rTNSS required the patients to record symptom severity over the previous 12 hours; iTNSS required patients to record symptom severity at the time immediately prior to the next dose. Morning and evening rTNSS scores were averaged over the treatment period and the difference from placebo in the change from baseline rTNSS was the primary efficacy endpoint. The morning iTNSS (AM iTNSS) reflects the TNSS at the end of the 24-hour dosing interval and is an indication of whether the effect was maintained over the 24-hour dosing interval. - Additional secondary efficacy variables were assessed, including the total ocular symptom score (TOSS) and the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). TOSS is calculated as the sum of the patients’ scoring of the 3 individual ocular symptoms (itching/burning, tearing/watering, and redness) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) as reflective (rTOSS) or instantaneous scores (iTOSS). To assess efficacy, rTOSS and AM iTOSS were evaluated as described above for the TNSS. Patients’ perceptions of disease-specific quality of life were evaluated through use of the RQLQ, which assesses the impact of allergic rhinitis treatment through 28 items in 7 domains (activities, sleep, non-nose/eye symptoms, practical problems, nasal symptoms, eye symptoms, and emotional) on a 7-point scale where 0 = no impairment and 6 = maximum impairment. An overall RQLQ score is calculated from the mean of all items in the instrument. An absolute difference of ≥0.5 in mean change from baseline over placebo is considered the minimally important difference (MID) for the RQLQ. - The dose-ranging trial was a 2-week trial that evaluated the efficacy of 4 dosages of fluticasone furoate nasal spray (440, 220, 110, and 55 mcg) in patients with seasonal allergic rhinitis. In this trial, each of the 4 dosages of fluticasone furoate nasal spray demonstrated greater decreases in the rTNSS than placebo, and the difference was statistically significant . - Each of the 4 dosages of fluticasone furoate nasal spray also demonstrated greater decreases in the AM iTNSS than placebo, and the difference between each of the 4 fluticasone furoate treatment groups and placebo was statistically significant, indicating that the effect was maintained over the 24-hour dosing interval. - Three clinical trials were designed to evaluate the efficacy of VERAMYST Nasal Spray 110 mcg once daily compared with placebo in patients with seasonal allergic rhinitis over a 2-week treatment period. In all 3 trials, VERAMYST Nasal Spray 110 mcg demonstrated a greater decrease from baseline in the rTNSS and AM iTNSS than placebo, and the difference from placebo was statistically significant. In terms of ocular symptoms, in all 3 seasonal allergic rhinitis trials, VERAMYST Nasal Spray 110 mcg demonstrated a greater decrease from baseline in the rTOSS than placebo and the difference from placebo was statistically significant. For the RQLQ in all 3 seasonal allergic rhinitis trials, VERAMYST Nasal Spray 110 mcg demonstrated greater decrease from baseline in the overall RQLQ than placebo, and the difference from placebo was statistically significant. The difference in the overall RQLQ score mean change from baseline between the groups treated with VERAMYST Nasal Spray and placebo ranged from -0.60 to -0.70 in the 3 trials, meeting the minimally important difference criterion. - One clinical trial was designed to evaluate the efficacy of VERAMYST Nasal Spray 110 mcg once daily compared with placebo in patients with perennial allergic rhinitis over a 4-week treatment period. VERAMYST Nasal Spray 110 mcg demonstrated a greater decrease from baseline in the rTNSS and AM iTNSS than placebo, and the difference from placebo was statistically significant. - Similar to patients with seasonal allergic rhinitis, the improvement of nasal symptoms with VERAMYST Nasal Spray in patients with perennial allergic rhinitis persisted for a full 24 hours, as evaluated by AM iTNSS immediately prior to the next dose. However, unlike the trials in patients with seasonal allergic rhinitis, patients with perennial allergic rhinitis who were treated with VERAMYST Nasal Spray 110 mcg did not demonstrate statistically significant improvement from baseline in rTOSS or in disease-specific quality of life as measured by the RQLQ compared with placebo. In addition, the overall RQLQ score mean change from baseline difference between the group treated with VERAMYST Nasal Spray and the placebo group was -0.23, which did not meet the minimally important difference of ≥0.5. - Onset of action was evaluated by frequent instantaneous TNSS assessments after the first dose in the clinical trials in patients with seasonal allergic rhinitis and perennial allergic rhinitis. Onset of action was generally observed within 24 hours in patients with seasonal allergic rhinitis. In patients with perennial rhinitis, onset of action was observed after 4 days of treatment. Continued improvement in symptoms was observed over approximately 1 and 3 weeks in patients with seasonal or perennial allergic rhinitis, respectively. - The efficacy and safety of VERAMYST Nasal Spray were evaluated in 1,112 children (633 boys and 479 girls), mean age of 8 years with seasonal or perennial allergic rhinitis in 2 controlled clinical trials. The pediatric patients were treated with VERAMYST Nasal Spray 55 or 110 mcg once daily for 2 to 12 weeks (n = 369 for each dose). The trials were similar in design to the trials conducted in adolescents and adults; however, the efficacy determination was made from patient- or parent/guardian-reported TNSS for children aged 6 to <12 years. Children treated with VERAMYST Nasal Spray generally exhibited greater decreases in nasal symptoms than placebo-treated patients. In seasonal allergic rhinitis, the difference in rTNSS was statistically significant only for the 110-mcg dose. In perennial allergic rhinitis, the difference in rTNSS was statistically significant only for the 55-mcg dose. Changes in rTOSS in the seasonal allergic rhinitis trial were not statistically significant compared with placebo for either dose. rTOSS was not assessed in the perennial allergic rhinitis trial. Table 5 displays the efficacy results from the clinical trials in patients with perennial allergic rhinitis and seasonal allergic rhinitis in children aged 6 to <12 years. Efficacy in children aged 2 to <6 years was supported by a numerical decrease in the rTNSS. # How Supplied - VERAMYST Nasal Spray, 27.5 mcg per spray, is supplied in a brown glass bottle enclosed in a nasal device with a nozzle and a mist-release button to actuate the spray in a box of 1 (NDC 0173-0753-00) with FDA-Approved Patient Labeling. - Each bottle contains a net fill weight of 10 g of white, liquid suspension and will provide 120 metered sprays. After priming , each spray delivers a fine mist containing 27.5 mcg of fluticasone furoate in 50 microliters of formulation through the nozzle. The contents of the bottle can be viewed through an indicator window. Shake the contents well before each use. The correct amount of medication in each spray cannot be assured before the initial priming and after 120 sprays have been used, even though the bottle is not completely empty. The nasal device should be discarded after 120 sprays have been used. ## Storage Store the device in the upright position with the cap in place between 15° and 30°C (59° and 86°F). Do not freeze or refrigerate. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Fluticasone furoate Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Fluticasone furoate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names VERAMYST # Look-Alike Drug Names There is limited information regarding Fluticasone furoate Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price

Ketazolam # Overview Ketazolam (marketed under the brand names Anseren, Ansieten, Ansietil, Marcen, Sedatival, Sedotime, Solatran and Unakalm) is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. # Therapeutic uses It is used for the treatment of anxiety and has similar effectiveness compared to diazepam. Ketazolam also appears to produce a reduced level of side effects such as sedation compared with diazepam and the side effects when they occur tend to be milder. Ketazolam is also an effective antispasmodic drug and is used for the treatment of spasticity. # Availability Ketazolam is not approved for sale in Australia, United Kingdom or the United States. In South Africa, GlaxoSmithKline markets ketazolam under its Solatran brand name. In Canada, ketazolam is listed in schedule IV of the Controlled Drugs and Substances Act, along with other benzodiazepines. # Tolerance and physical dependence Chronic use of ketazolam as with other benzodiazepines can lead to physical dependence and the appearance of the benzodiazepine withdrawal syndrome upon cessation of use or decrease in dose. Tolerance to ketazolam's therapeutic effects occurs over a period of 15 days. # Contraindications and special caution Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders. # Pharmacokinetics Ketazolam breaks down in the blood to diazepam which breaks down to demoxepam which breaks down to desmethyldiazepam. # Warnings The U.S. Food and Drug Administration warns that in Spain, ketazolam marketed as Marcen may sometimes be mistakenly confused with Narcan. # Legal status Ketazolam is a List 3 drug under the Betäubungsmittelgesetz, like almost all benzodiazepines in Germany. Ketazolam is a List II drugs of the Opium Law in the Netherlands. Ketazolam is a Schedule IV drug under the Controlled Substances Act in the US.

1,2-Dichloroethane # Overview The chemical compound 1,2-dichloroethane, commonly known by its old name of ethylene dichloride (EDC), is a chlorinated hydrocarbon, mainly used to produce vinyl chloride monomer (VCM, chloroethene), the major precursor for PVC production. It is a colourless liquid with a chloroform-like odour. 1,2-Dichloroethane is also used generally as an intermediate for other organic chemical compounds, and as a solvent. # History In 1794, a group of four Dutch friends under the name of Gezelschap der Hollandsche Scheikensleishen (Society of Dutch Chemists) consisted of physician Jan Rudolph Deerman, merchant Adriaan Paets van Troopstwijkity, chemist Anthoni Lauwerenburgest and botanist Nicolaas Bondtitigutrud. They were the first to produce 1,2-dichloroethane from olefiant gas (oil-making gas, ethylene) and chlorine gas. Although the Gezelschap in practice didn't do much in-depth scientific research, they and their publications where highly regarded. Part of that acknowledgement is that 1,2-dichloroethane has been called Dutch oil in old chemistry. # Chemistry 1,2-Dichloroethane has chemical formula Template:Carbon2Template:Hydrogen4Template:Chlorine2. Cf. 1,1-Dichloroethane (ethylidene dichloride). # Production Every year 17.5 million tons of 1,2-dichloroethane are produced in the United States, Western Europe and Japan. This is primarily achieved through the iron(III) chloride catalysed reaction of ethene (ethylene) and chlorine. In subsequent reactions, notably to vinyl chloride (chloroethene), hydrogen chloride is formed and re-used in a copper(II) chloride catalysed reaction, to also produce 1,2-dichloroethane from ethene and oxygen. # Uses ## Vinyl chloride monomer (VCM) production With approximately 80% of the world's consumption of 1,2-dichloroethane, the major application is in the production of vinyl chloride monomer (VCM, chloroethene), which is the precursor to polyvinyl chloride under the formation of hydrogen chloride. The hydrogen chloride can be re-used in the production process, in the formation of more 1,2-dichloroethane (see Production). ## Other Uses As a good apolar aprotic solvent, 1,2-dichloroethane is used as degreaser and paint remover. As a useful 'building block' reagent, it is used as an intermediate in the production of various organic compounds. It is also used as a reagent as an electrophillic source of chlorine, with elimination of ethene and chloride. Historically, it was used as an anti-knock additive in leaded fuels. # Safety 1,2-dichloroethane is toxic (especially by inhalation due to its high vapour pressure), corrosive, highly flammable, and possibly carcinogenic. Its high solubility and 50-year half-life in anoxic aquifers make it a perennial pollutant and health risk that is very expensive to treat conventionally, requiring a method of bioremediation.

American Journal of Psychiatry The American Journal of Psychiatry (AJP) is the most widely read psychiatric journal in the world. It covers topics on biological psychiatry, treatment innovations, forensic, ethical, economic, and social issues. Official American Psychiatric Association reports appear from time to time. The AJP is published monthly, using a peer-reviewed process. In addition to articles, it publishes letters to the editor and book reviews. Its original title was the American Journal of Insanity, changed to the current form in the July issue of 1921. # Suicide Rate On September 6, 2007, the Centers for Disease Control and Prevention reported suicide rate in American adolescents (especially girls, 10 to 24 years old) increased 8% (2003 to 2004), the largest jump in 15 years. Specifically, in 2004 - 4,599 suicides in Americans ages 10 to 24, up from 4,232 in 2003, for a rate of 7.32 per 100,000 people that age. Before, the rate dropped to 6.78 per 100,000 in 2003 from 9.48 per 100,000 in 1990. The findings also reported that antidepressant drugs reduced suicide risk than increase it. Psychiatrists found that the increase is due to the decline in prescriptions of antidepressant drugs like Prozac to young people since 2003, leaving more cases of serious depression untreated. In a December 2006 study, The American Journal of Psychiatry said that a decrease in antidepressant prescriptions to minors of just a few percentage points coincided with a 14 percent increase in suicides in the United States; in the Netherlands, the suicide rate was 50% up, upon prescription drop.

Indiana School for the Deaf Indiana School for the Deaf (ISD) is a fully accredited school for the Deaf and hard of hearing, located in Indianapolis, Indiana. # History When the first school for the Deaf was established in Indiana, it was not called Indiana School for the Deaf. It was named Willard School, after the founder, William Willard. William Willard was a Deaf teacher who taught at Ohio School for the Deaf in Columbus, Ohio. He travelled to Indianapolis in May of 1843 to propose the establishment of a Deaf School. Once he had the support of the General Assembly, he recruited approximately twelve students. He and his wife, Eliza, were teachers. Eventually, the school had grown and a law which was passed in 1846 officially established the Willard School as the sixth state school for the Deaf and the first Deaf school to provide free education to Deaf and hard of hearing students. The school had actually moved a few times in different locations, when finally, the school was built on an 80 acre (32 hectare) property on East 42nd Street. The name was changed to Indiana School for the Deaf. The school's main buildings on the current campus are registered as historic landmarks. For more information on the History of ISD, please scroll down to the External Links section. # Philosophy The Bilingual/Bicultural Philosophy provides language acquisition and facilitates proficiency in two languages, American Sign Language (ASL), and English. By providing an enriched academic and cultural learning environment, its Deaf and Hard-of-Hearing students develop a sense of identity within the Deaf community. Students also develop the knowledge, skills, and attitudes to function effectively with members of a multicultural, diversified community. # Academics ISD offers several programs ranging from infants to high school. They are as follows: Parent Infant Program, Preschool, Elementary, Middle School, and High School. The Parent Infant Program works closely with parents and their deaf or hard of hearing children from ages 0 to 3. When a student reaches 18 months of age, he or she can enroll at ISD as an official student. Preschool handles children up until Pre-Kindergarten. Elementary provides academics and activities for Kindergarten through 5th grade students. Middle school hosts grades 6 to 8, and High School hosts grades 9 through 12. # Residency ISD is also a residential school. It has dormitories where students reside throughout the week. Students arrive on Sundays and depart on Fridays. Dormitories are for students who live far enough not to be able to travel by bus every day to school. There are dormitories for male and female students: Preschool, Elementary, Middle School, and High School. ISD's residential programs offers extracurricular activities, peer interaction, student growth and development, achievement, and more. # Athletics ISD offers several athletics starting from 5th grade to 12th grade. There are sports for both female and male students. - Male Sports Football Cross Country Wrestling Basketball Baseball Track and Field Swimming - Football - Cross Country - Wrestling - Basketball - Baseball - Track and Field - Swimming - Female Sports Volleyball Basketball Cheerleading Track and Field Swimming Softball - Volleyball - Basketball - Cheerleading - Track and Field - Swimming - Softball

Pseudo-Cushing's syndrome (patient information) For the WikiDoc page for this topic, click here # Overview Pseudo-Cushing's syndrome is a rare endocrine disorder in which patients display the signs, symptoms, and abnormal hormone levels seen in Cushing's syndrome. However, it is not a disease caused by the problem of the hypothalamic-pituitary-adrenal axis, but an idiopathic condition. The mechanism of pseudo-Cushing's syndrome remains unclear. Studies demonstrate that it is associated with some conditions, such as alcoholism or alcohol withdrawal, severe stresses, and some psychiatric conditions. Signs and symptoms of pseudo-Cushing's syndrome are similar to true Cushing's syndrome, such as truncal obesity, plethoric moon face, buffalo hump, thin skin, hypertension, increased appetite, weight gain, mood swings and fatigue. Cortisol level in salivary, urinary and blood may help diagnose. There is no specific medications for this disorder. Prognosis of pseudo-Cushing's syndrome depends on the cause and the person. # How do I know if I have pseudo-Cushing's syndrome and what are the symptoms of pseudo-Cushing's syndrome? Signs of patients with pseudo-Cushing's syndrome are similar to Cushing's syndrome. They include the following characteristics. - Truncal obesity, plethoric moon face, buffalo hump - Supraclavicular fat pads - Hirsutism and menstrual irregularities in women - Thin skin with easy bruising and wide, purplish striae - Hypertension - Increased appetite, weight gain - Depression, or mood swings, anxiety - Fatigue - Trouble sleeping # Who is at risk for pseudo-Cushing's syndrome? - Alcoholism or alcohol withdrawal - Severe stresses - Psychiatric conditions such as depression, panic disorders and psychotic conditions. # How to know you have pseudo-Cushing's syndrome? - Salivary cortisol level: Measurement of ate-night salivary cortisol concentrations can be used as a screening test in suspected pseudo-Cushing's syndrome. - The 24-hour urinary free cortisol (UFC): In this test, a patient’s urine is collected several times over a 24-hour period and tested for cortisol. Patients with pseudo-Cushing's syndrome may show moderately increased in the 24-hour urinary free cortisol (UFC) level. - Blood level of cortisol: Patients with pseudo-Cushing's syndrome may show elevated levels of serum cortisol in the morning and evening and the morning level is not suppressed to less than 5 µg/dL by 1 mg dexamethasone administered at midnight. A midnight cortisol level of less than 7.5 µg/dL is an important difference between pseudo-Cushing and true Cushing's syndrome. - Liver function: Elevation of serum transaminase levels suggest alcohol-induced hepatitis. - Blood alcohol level: Because many patients of pseudo-Cushing's syndrome are caused by alcohol abuse, blood alcohol level may be helpful. # When to seek urgent medical care? Call your health care provider if symptoms of pseudo-Cushing's syndrome develop. If you experience either of the following symptoms, seeking urgent medical care as soon as possible: - Severe hypertension # Treatment options Treatments of pseudo-Cushing's syndrome depend on the cause. There is no specific medications for this disorder. - Anticipate and prevent alcohol withdrawal syndrome. - Treat psychiatric conditions, relieve stresses. # Diseases with similar symptoms - Cushing's syndrome - Depression # Where to find medical care for pseudo-Cushing's syndrome? Directions to Hospitals Treating pseudo-Cushing's syndrome # Prevention of pseudo-Cushing's syndrome - Avoidance of alcohol abuse. - Avoidance too much pressure. If needed, go to see your psychologist. # What to expect (Outook/Prognosis)? Prognosis of pseudo-Cushing's syndrome varies, depending on the cause and the person. With abstinence from alcohol, all biochemical abnormalities return to reference ranges. But patients with chronic alcoholism often relapse.

Germicidal lamp # Overview A germicidal lamp is a special type of lamp which produces ultraviolet light (UVC). This short-wave ultraviolet light ionizes oxygen to produce ozone and can kill many surface pathogens. There are two common types available: - Low pressure lamps - Medium pressure lamps # Low pressure lamps Low-pressure lamps are very similar to a fluorescent lamp, with a wavelength of 253.7 nm. The most common form of germicidal lamp looks similar to an ordinary fluorescent lamp but the tube contains no fluorescent phosphor. In addition, rather than being made of ordinary borosilicate glass, the tube is made of fused quartz. These two changes combine to allow the 253.7 nm ultraviolet light produced by the mercury arc to pass out of the lamp unmodified (whereas, in common fluorescent lamps, it causes the phosphor to fluoresce, producing visible light). Germicidal lamps still produce a small amount of visible light due to other mercury radiation bands. An older design looks like an incandescent lamp but with the envelope containing a few droplets of mercury. In this design, the incandescent filament heats the mercury, producing a vapor which eventually allows an arc to be struck, short circuiting the incandescent filament. # Medium pressure lamps Medium-pressure lamps are much more similar to HID lamps than fluorescent lamps. These lamps radiate a broad-band UV-C radiation, rather than a single line. They are widely used in industrial water treatment, because they are very intense radiation sources. They are not as efficient as low-pressure lamps but low-pressure lamps are very hard to manufacture in high wattages (over one kW). Medium-pressure lamps produces very bright bluish white light. # Auxiliary equipment As with all gas discharge lamps, all of the styles of germicidal lamps exhibit negative resistance and require the use of an external ballast to regulate the current flow through them. The older lamps that resembled an incandescent lamp were often operated in series with an ordinary 40 W incandescent "appliance" lamp; the incandescent lamp acted as the ballast for the germicidal lamp. # Uses Germicidal lamps are used to sterilize workspaces and tools used in biology laboratories and medical facilities. They are also used wherever ozone is desired, for example, in the sanitizing systems of hot tubs and aquariums. They are also used by geologists to provoke fluorescence in mineral samples, aiding in their identification. In this application, the light produced by the lamp is usually filtered to remove as much visible light as possible, leaving just the UV light. The light produced by germicidal lamps is also used to erase EPROMs; the ultraviolet photons are sufficiently energetic to allow the electrons trapped on the transistors' floating gates to tunnel through the gate insulation, eventually removing the stored charge that represents binary ones and zeroes. Germicidal lamps are also used in waste water treatment in order to kill microorganisms. # Safety concerns Short-wave UV light is harmful to humans. In addition to causing sunburn and (over time) skin cancer, this light can produce extremely painful inflammation of the cornea of the eye, which may lead to temporary or permanent vision impairment. It can also damage the retina of the eye. For this reason, the light produced by a germicidal lamp must be carefully shielded against both direct viewing and reflections and dispersed light that might be viewed. cs:Germicidní lampa hu:Germicid lámpák

Morvan's syndrome # Overview Morvan's syndrome (or fibrillary chorea) is a rare disease named after nineteenth century French physician Augustin Marie Morvan (1819-1897). # Symptoms Morvan's syndrome is characterised by status epilepticus & tonic-clonic epilepsy (grand mal) plus neuromyotonia (involuntary fibrillary contraction of muscles at rest), autonomic nervous system dysfunction, central nervous system dysfunction and endocrine system problems. Major central nervous system problems are sleep disorder, confusion, amnesia, hallucinations and delusions. One of the most striking symptoms is a decreased need for sleep. In 1974 a neurobiologist Michel Jouvet reported a case of a 27-year-old man with Morvan's syndrome who required no sleep and rarely felt tired for periods of many months yet would experience daily hallucinations between 9 P.M. and 11 P.M. as well as pain and blood vessel constriction. # Causes Some cases with this syndrome have been suggested to be caused by an autoimmune disease linked to VGKC antibodies and antibodies to potassium channels, others are caused by paraneoplastic syndromes or are side effects of procedures such as a thymectomy. # Treatment Treatment is variable and many cases remit spontaneously. Still others require plasmapheresis, immunosuppression, thymectomy and immunomodulating treatments. Obviously, if the cause is an underlying malignancy, the disease may remit once the malignancy itself is treated or surgically removed. # Comorbid conditions Some conditions such as myasthenia gravis are often also present during the condition as are tumors particularly thymus tumors

ICD-10 Chapter XI: Diseases of the digestive system # K00-K93 - Diseases of the digestive system ## (K00-K14) Diseases of oral cavity, salivary glands and jaws - (K00) Disorders of tooth development and eruption (K00.0) Anodontia (K00.1) Supernumerary teeth (K00.2) Abnormalities of size and form of teeth Concrescence Tooth fusion Dens evaginatus Dens invaginatus Enamel pearls Macrodontia Microdontia Taurodontism (K00.4) Disturbances in tooth formation Dilaceration of tooth Enamel hypoplasia Regional odontodysplasia Turner's tooth (K00.5) Hereditary disturbances in tooth structure, not elsewhere classified Amelogenesis imperfecta Dentinogenesis imperfecta Odontogenesis imperfecta Dentinal dysplasia Shell teeth (K00.6) Disturbances in tooth eruption (K00.7) Teething syndrome (K00.8) Other disorders of tooth development (K00.9) Disorder of tooth development, unspecified - (K00.0) Anodontia - (K00.1) Supernumerary teeth - (K00.2) Abnormalities of size and form of teeth Concrescence Tooth fusion Dens evaginatus Dens invaginatus Enamel pearls Macrodontia Microdontia Taurodontism - Concrescence - Tooth fusion - Dens evaginatus - Dens invaginatus - Enamel pearls - Macrodontia - Microdontia - Taurodontism - (K00.4) Disturbances in tooth formation Dilaceration of tooth Enamel hypoplasia Regional odontodysplasia Turner's tooth - Dilaceration of tooth - Enamel hypoplasia - Regional odontodysplasia - Turner's tooth - (K00.5) Hereditary disturbances in tooth structure, not elsewhere classified Amelogenesis imperfecta Dentinogenesis imperfecta Odontogenesis imperfecta Dentinal dysplasia Shell teeth - Amelogenesis imperfecta - Dentinogenesis imperfecta - Odontogenesis imperfecta - Dentinal dysplasia - Shell teeth - (K00.6) Disturbances in tooth eruption - (K00.7) Teething syndrome - (K00.8) Other disorders of tooth development - (K00.9) Disorder of tooth development, unspecified - (K01) Embedded and impacted teeth (K01.0) Embedded teeth (K01.1) impacted teeth - (K01.0) Embedded teeth - (K01.1) impacted teeth - (K02) Dental caries (K02.0) Caries limited to enamel (K02.1) Caries of dentine (K02.2) Caries of cementum (K02.3) Arrested dental caries (K02.4) Odontoclasia (K02.8) Other dental caries (K02.9) Dental caries, unspecified - (K02.0) Caries limited to enamel - (K02.1) Caries of dentine - (K02.2) Caries of cementum - (K02.3) Arrested dental caries - (K02.4) Odontoclasia - (K02.8) Other dental caries - (K02.9) Dental caries, unspecified - (K03) Other diseases of hard tissues of teeth (K03.0) Excessive attrition of teeth (K03.1) Abrasion of teeth (K03.2) Erosion of teeth (K03.3) Pathological resorption of teeth (K03.4) Hypercementosis (K03.5) Ankylosis of teeth (K03.6) Deposits (accretions) on teeth (K03.7) Posteruptive colour changes of dental hard tissues (K03.8) Other specified diseases of hard tissues of teeth (K03.9) Disease of hard tissues of teeth, unspecified - (K03.0) Excessive attrition of teeth - (K03.1) Abrasion of teeth - (K03.2) Erosion of teeth - (K03.3) Pathological resorption of teeth - (K03.4) Hypercementosis - (K03.5) Ankylosis of teeth - (K03.6) Deposits (accretions) on teeth - (K03.7) Posteruptive colour changes of dental hard tissues - (K03.8) Other specified diseases of hard tissues of teeth - (K03.9) Disease of hard tissues of teeth, unspecified - (K04) Diseases of pulp and periapical tissues (K04.0) Pulpitis (K04.1) Necrosis of pulp (K04.2) Pulp degeneration (K04.3) Abnormal hard tissue formation in pulp (K04.4) Acute apical periodontitis of pulpal origin (K04.5) Chronic apical periodontitis (K04.6) Periapical abscess with sinus (K04.7) Periapical abscess without sinus (K04.8) Radicular cyst (K04.9) Other and unspecified diseases of pulp and periapical tissues - (K04.0) Pulpitis - (K04.1) Necrosis of pulp - (K04.2) Pulp degeneration - (K04.3) Abnormal hard tissue formation in pulp - (K04.4) Acute apical periodontitis of pulpal origin - (K04.5) Chronic apical periodontitis - (K04.6) Periapical abscess with sinus - (K04.7) Periapical abscess without sinus - (K04.8) Radicular cyst - (K04.9) Other and unspecified diseases of pulp and periapical tissues - (K05) Gingivitis and periodontal diseases (K05.0) Acute gingivitis (K05.1) Chronic gingivitis (K05.2) Acute periodontitis (K05.3) Chronic periodontitis (K05.4) Periodontosis (K05.5) Other periodontal diseases (K05.6) Periodontal disease, unspecified - (K05.0) Acute gingivitis - (K05.1) Chronic gingivitis - (K05.2) Acute periodontitis - (K05.3) Chronic periodontitis - (K05.4) Periodontosis - (K05.5) Other periodontal diseases - (K05.6) Periodontal disease, unspecified - (K06) Other disorders of gingiva and edentulous alveolar ridge (K06.0) Gingival recession (K06.1) Gingival enlargement (K06.2) Gingival and edentulous alveolar ridge lesions associated with trauma (K06.8) Other specified disorders of gingiva and edentulous alveolar ridge Fibrous epulis Flabby ridge Giant cell epulis Peripheral giant cell granuloma Pyogenic granuloma of gingiva (K06.9) Disorder of gingiva and edentulous alveolar ridge, unspecified - (K06.0) Gingival recession - (K06.1) Gingival enlargement - (K06.2) Gingival and edentulous alveolar ridge lesions associated with trauma - (K06.8) Other specified disorders of gingiva and edentulous alveolar ridge Fibrous epulis Flabby ridge Giant cell epulis Peripheral giant cell granuloma Pyogenic granuloma of gingiva - Fibrous epulis - Flabby ridge - Giant cell epulis - Peripheral giant cell granuloma - Pyogenic granuloma of gingiva - (K06.9) Disorder of gingiva and edentulous alveolar ridge, unspecified - (K07) Dentofacial anomalies (including malocclusion) (K07.0) Major anomalies of jaw size mandibular hyperplasia maxillary hypoplasia mandibular hyperplasia maxillary hypoplasia Macrognathism (mandibular)(maxillary) Micrognathism (mandibular)(maxillary) (K07.1) Anomalies of jaw-cranial base relationship Asymmetry of jaw Prognathism (mandibular)(maxillary) Retrognathism (mandibular)(maxillary) (K07.2) Anomalies of dental arch relationship Crossbite (anterior)(posterior) Disto-occlusion Mesio-occlusion Midline deviation of dental arch Openbite (anterior)(posterior) Overbite (excessive) Overjet Posterior lingual occlusion of mandibular teeth (K07.3) Anomalies of tooth position Crowding of tooth or teeth Diastema of tooth or teeth Displacement of tooth or teeth Rotation of tooth or teeth Abnormal spacing of tooth or teeth Transposition of tooth or teeth Impacted or embedded teeth with abnormal position of such teeth or adjacent teeth (K07.4) Malocclusion, unspecified (K07.5) Dentofacial functional abnormalities Abnormal jaw closure Malocclusion due to abnormal swallowing Malocclusion due tomouth breathing Malocclusion due totongue, lip or finger habits (K07.6) Temporomandibular joint disorders Costen's complex or syndrome Derangement of temporomandibular joint Snapping jaw Temporomandibular joint-pain-dysfunction syndrome (K07.8) Other dentofacial anomalies (K07.9) Dentofacial anomaly, unspecified - (K07.0) Major anomalies of jaw size mandibular hyperplasia maxillary hypoplasia mandibular hyperplasia maxillary hypoplasia Macrognathism (mandibular)(maxillary) Micrognathism (mandibular)(maxillary) - mandibular hyperplasia - maxillary hypoplasia - mandibular hyperplasia - maxillary hypoplasia - Macrognathism (mandibular)(maxillary) - Micrognathism (mandibular)(maxillary) - (K07.1) Anomalies of jaw-cranial base relationship Asymmetry of jaw Prognathism (mandibular)(maxillary) Retrognathism (mandibular)(maxillary) - Asymmetry of jaw - Prognathism (mandibular)(maxillary) - Retrognathism (mandibular)(maxillary) - (K07.2) Anomalies of dental arch relationship Crossbite (anterior)(posterior) Disto-occlusion Mesio-occlusion Midline deviation of dental arch Openbite (anterior)(posterior) Overbite (excessive) Overjet Posterior lingual occlusion of mandibular teeth - Crossbite (anterior)(posterior) - Disto-occlusion - Mesio-occlusion - Midline deviation of dental arch - Openbite (anterior)(posterior) - Overbite (excessive) - Overjet - Posterior lingual occlusion of mandibular teeth - (K07.3) Anomalies of tooth position Crowding of tooth or teeth Diastema of tooth or teeth Displacement of tooth or teeth Rotation of tooth or teeth Abnormal spacing of tooth or teeth Transposition of tooth or teeth Impacted or embedded teeth with abnormal position of such teeth or adjacent teeth - Crowding of tooth or teeth - Diastema of tooth or teeth - Displacement of tooth or teeth - Rotation of tooth or teeth - Abnormal spacing of tooth or teeth - Transposition of tooth or teeth - Impacted or embedded teeth with abnormal position of such teeth or adjacent teeth - (K07.4) Malocclusion, unspecified - (K07.5) Dentofacial functional abnormalities Abnormal jaw closure Malocclusion due to abnormal swallowing Malocclusion due tomouth breathing Malocclusion due totongue, lip or finger habits - Abnormal jaw closure - Malocclusion due to abnormal swallowing - Malocclusion due tomouth breathing - Malocclusion due totongue, lip or finger habits - (K07.6) Temporomandibular joint disorders Costen's complex or syndrome Derangement of temporomandibular joint Snapping jaw Temporomandibular joint-pain-dysfunction syndrome - Costen's complex or syndrome - Derangement of temporomandibular joint - Snapping jaw - Temporomandibular joint-pain-dysfunction syndrome - (K07.8) Other dentofacial anomalies - (K07.9) Dentofacial anomaly, unspecified - (K08) Other disorders of teeth and supporting structures (K08.0) Exfoliation of teeth due to systemic causes (K08.1) Loss of teeth due to accident, extraction or local periodontal disease (K08.2) Atrophy of edentulous alveolar ridge (K08.3) Retained dental root (K08.8) Other specified disorders of teeth and supporting structures Enlargement of alveolar ridge NOS Irregular alveolar process Toothache NOS (K08.9) Disorder of teeth and supporting structures, unspecified - (K08.0) Exfoliation of teeth due to systemic causes - (K08.1) Loss of teeth due to accident, extraction or local periodontal disease - (K08.2) Atrophy of edentulous alveolar ridge - (K08.3) Retained dental root - (K08.8) Other specified disorders of teeth and supporting structures Enlargement of alveolar ridge NOS Irregular alveolar process Toothache NOS - Enlargement of alveolar ridge NOS - Irregular alveolar process - Toothache NOS - (K08.9) Disorder of teeth and supporting structures, unspecified - (K09) Cysts of oral region, not elsewhere classified (K09.0) Developmental odontogenic cysts (K09.1) Developmental (nonodontogenic) cysts of oral region (K09.2) Other cysts of jaw (K09.8) Other cysts of oral region, not elsewhere classified (K09.9) Cyst of oral region, unspecified - (K09.0) Developmental odontogenic cysts - (K09.1) Developmental (nonodontogenic) cysts of oral region - (K09.2) Other cysts of jaw - (K09.8) Other cysts of oral region, not elsewhere classified - (K09.9) Cyst of oral region, unspecified - (K10) Other diseases of jaws (K10.0) Developmental disorders of jaws Torus mandibularis Torus palatinus (K10.1) Giant cell granuloma, central (K10.2) Inflammatory conditions of jaws (K10.3) Alveolitis of jaws (K10.8) Other specified diseases of jaws (K10.9) Disease of jaws, unspecified - (K10.0) Developmental disorders of jaws Torus mandibularis Torus palatinus - Torus mandibularis - Torus palatinus - (K10.1) Giant cell granuloma, central - (K10.2) Inflammatory conditions of jaws - (K10.3) Alveolitis of jaws - (K10.8) Other specified diseases of jaws - (K10.9) Disease of jaws, unspecified - (K11) Diseases of salivary glands (K11.0) Atrophy of salivary gland (K11.1) Hypertrophy of salivary gland (K11.2) Sialadenitis (K11.3) Abscess of salivary gland (K11.4) Fistula of salivary gland (K11.5) Sialolithiasis (K11.6) Mucocele of salivary gland Ranula (K11.7) Disturbances of salivary secretion Hypoptyalism Ptyalism Xerostomia (K11.8) Other diseases of salivary glands Benign lymphoepithelial lesion of salivary gland Mikulicz' disease Necrotizing sialometaplasia Sialectasia - (K11.0) Atrophy of salivary gland - (K11.1) Hypertrophy of salivary gland - (K11.2) Sialadenitis - (K11.3) Abscess of salivary gland - (K11.4) Fistula of salivary gland - (K11.5) Sialolithiasis - (K11.6) Mucocele of salivary gland Ranula - Ranula - (K11.7) Disturbances of salivary secretion Hypoptyalism Ptyalism Xerostomia - Hypoptyalism - Ptyalism - Xerostomia - (K11.8) Other diseases of salivary glands Benign lymphoepithelial lesion of salivary gland Mikulicz' disease Necrotizing sialometaplasia Sialectasia - Benign lymphoepithelial lesion of salivary gland - Mikulicz' disease - Necrotizing sialometaplasia - Sialectasia - (K11.9) Disease of salivary gland, unspecified - (K11.9) Disease of salivary gland, unspecified - (K12) Stomatitis and related lesions (K12.0) Recurrent oral aphthae (K12.1) Other forms of stomatitis (K12.2) Cellulitis and abscess of mouth - (K12.0) Recurrent oral aphthae - (K12.1) Other forms of stomatitis - (K12.2) Cellulitis and abscess of mouth - (K13) Other diseases of lip and oral mucosa (K13.0) Diseases of lips Cheilitis Cheilodynia Cheilosis Perlèche NEC (K13.1) Cheek and lip biting (K13.2) Leukoplakia and other disturbances of oral epithelium, including tongue Erythroplakia (K13.3) Hairy leukoplakia (K13.4) Granuloma and granuloma-like lesions of oral mucosa Verrucous xanthoma (K13.5) Oral submucous fibrosis (K13.6) Irritative hyperplasia of oral mucosa (K13.7) Other and unspecified lesions of oral mucosa - (K13.0) Diseases of lips Cheilitis Cheilodynia Cheilosis Perlèche NEC - Cheilitis - Cheilodynia - Cheilosis - Perlèche NEC - (K13.1) Cheek and lip biting - (K13.2) Leukoplakia and other disturbances of oral epithelium, including tongue Erythroplakia - Erythroplakia - (K13.3) Hairy leukoplakia - (K13.4) Granuloma and granuloma-like lesions of oral mucosa Verrucous xanthoma - Verrucous xanthoma - (K13.5) Oral submucous fibrosis - (K13.6) Irritative hyperplasia of oral mucosa - (K13.7) Other and unspecified lesions of oral mucosa - (K14) Diseases of tongue (K14.0) Glossitis (K14.1) Geographic tongue (K14.2) Median rhomboid glossitis (K14.3) Hypertrophy of tongue papillae Black hairy tongue (K14.4) Atrophy of tongue papillae (K14.5) Plicated tongue Fissured tongue (K14.6) Glossodynia (K14.8) Other diseases of tongue (K14.9) Disease of tongue, unspecified - (K14.0) Glossitis - (K14.1) Geographic tongue - (K14.2) Median rhomboid glossitis - (K14.3) Hypertrophy of tongue papillae Black hairy tongue - Black hairy tongue - (K14.4) Atrophy of tongue papillae - (K14.5) Plicated tongue Fissured tongue - Fissured tongue - (K14.6) Glossodynia - (K14.8) Other diseases of tongue - (K14.9) Disease of tongue, unspecified ## (K20-K31) Diseases of oesophagus, stomach and duodenum - (K20) esophagitis - (K21) Gastro-oesophageal reflux disease - (K22) Other diseases of oesophagus (K22.0) Achalasia of cardia (K22.1) Ulcer of oesophagus (K22.2) Oesophageal obstruction (K22.3) Perforation of oesophagus (K22.4) Dyskinesia of oesophagus (K22.5) Diverticulum of oesophagus, acquired (K22.6) Gastro-oesophageal laceration-haemorrhage syndrome (K22.7) Barrett's oesophagus (K22.8) Other specified diseases of oesophagus (K22.9) Disease of oesophagus, unspecified - (K22.0) Achalasia of cardia - (K22.1) Ulcer of oesophagus - (K22.2) Oesophageal obstruction - (K22.3) Perforation of oesophagus - (K22.4) Dyskinesia of oesophagus - (K22.5) Diverticulum of oesophagus, acquired - (K22.6) Gastro-oesophageal laceration-haemorrhage syndrome - (K22.7) Barrett's oesophagus - (K22.8) Other specified diseases of oesophagus - (K22.9) Disease of oesophagus, unspecified - (K23) Disorders of oesophagus in diseases classified elsewhere - (K25) Gastric ulcer - (K26) Duodenal ulcer - (K27) Peptic ulcer, site unspecified - (K28) Gastrojejunal ulcer - (K29) Gastritis and duodenitis (K29.0) Acute haemorrhagic gastritis (K29.1) Other acute gastritis (K29.2) Alcoholic gastritis (K29.3) Chronic superficial gastritis (K29.4) Chronic atrophic gastritis (K29.5) Chronic gastritis, unspecified (K29.6) Other gastritis (K29.7) Gastritis, unspecified (K29.8) Duodenitis (K29.9) Gastroduodenitis, unspecified - (K29.0) Acute haemorrhagic gastritis - (K29.1) Other acute gastritis - (K29.2) Alcoholic gastritis - (K29.3) Chronic superficial gastritis - (K29.4) Chronic atrophic gastritis - (K29.5) Chronic gastritis, unspecified - (K29.6) Other gastritis - (K29.7) Gastritis, unspecified - (K29.8) Duodenitis - (K29.9) Gastroduodenitis, unspecified - (K30) Dyspepsia - (K31) Other diseases of stomach and duodenum (K31.0) Acute dilatation of stomach (K31.1) Adult hypertrophic pyloric stenosis (K31.2) Hourglass stricture and stenosis of stomach (K31.3) Pylorospasm, not elsewhere classified (K31.4) Gastric diverticulum (K31.5) Obstruction of duodenum (K31.6) Fistula of stomach and duodenum (K31.7) Polyp of stomach and duodenum (K31.8) Other specified diseases of stomach and duodenum Achlorhydria Gastroptosis Hourglass contraction of stomach (K31.9) Disease of stomach and duodenum, unspecified - (K31.0) Acute dilatation of stomach - (K31.1) Adult hypertrophic pyloric stenosis - (K31.2) Hourglass stricture and stenosis of stomach - (K31.3) Pylorospasm, not elsewhere classified - (K31.4) Gastric diverticulum - (K31.5) Obstruction of duodenum - (K31.6) Fistula of stomach and duodenum - (K31.7) Polyp of stomach and duodenum - (K31.8) Other specified diseases of stomach and duodenum Achlorhydria Gastroptosis Hourglass contraction of stomach - Achlorhydria - Gastroptosis - Hourglass contraction of stomach - (K31.9) Disease of stomach and duodenum, unspecified ## (K35-K38) Diseases of appendix - (K35) Acute appendicitis (K35.0) Acute appendicitis with generalized peritonitis (K35.1) Acute appendicitis with peritoneal abscess (K35.9) Acute appendicitis, unspecified - (K35.0) Acute appendicitis with generalized peritonitis - (K35.1) Acute appendicitis with peritoneal abscess - (K35.9) Acute appendicitis, unspecified - (K36) Other appendicitis - (K37) Unspecified appendicitis - (K38) Other diseases of appendix (K38.0) Hyperplasia of appendix (K38.1) Appendicular concretions Faecalith Stercolith (K38.2) Diverticulum of appendix (K38.3) Fistula of appendix (K38.8) Other specified diseases of appendix Intussusception of appendix (K38.9) Disease of appendix, unspecified - (K38.0) Hyperplasia of appendix - (K38.1) Appendicular concretions Faecalith Stercolith - Faecalith - Stercolith - (K38.2) Diverticulum of appendix - (K38.3) Fistula of appendix - (K38.8) Other specified diseases of appendix Intussusception of appendix - Intussusception of appendix - (K38.9) Disease of appendix, unspecified ## (K40-K46) Hernia - (K40) Inguinal hernia - (K41) Femoral hernia - (K42) Umbilical hernia - (K43) Ventral hernia - (K44) Diaphragmatic hernia - (K45) Other abdominal hernia Lumbar hernia - Lumbar hernia - (K46) Unspecified abdominal hernia ## (K50-K52) Noninfective enteritis and colitis - (K50) Crohn's disease (regional enteritis) (K50.0) Crohn's disease of small intestine (K50.1) Crohn's disease of large intestine (K50.8) Other Crohn's disease (K50.9) Crohn's disease, unspecified - (K50.0) Crohn's disease of small intestine - (K50.1) Crohn's disease of large intestine - (K50.8) Other Crohn's disease - (K50.9) Crohn's disease, unspecified - (K51) Ulcerative colitis (K51.0) Ulcerative (chronic) enterocolitis (K51.1) Ulcerative (chronic) ileocolitis (K51.2) Ulcerative (chronic) proctitis (K51.3) Ulcerative (chronic) rectosigmoiditis (K51.4) Pseudopolyposis of colon (K51.5) Mucosal proctocolitis (K51.8) Other ulcerative colitis (K51.9) Ulcerative colitis, unspecified Ulcerative enteritis NOS - (K51.0) Ulcerative (chronic) enterocolitis - (K51.1) Ulcerative (chronic) ileocolitis - (K51.2) Ulcerative (chronic) proctitis - (K51.3) Ulcerative (chronic) rectosigmoiditis - (K51.4) Pseudopolyposis of colon - (K51.5) Mucosal proctocolitis - (K51.8) Other ulcerative colitis - (K51.9) Ulcerative colitis, unspecified Ulcerative enteritis NOS - Ulcerative enteritis NOS - (K52) Other noninfective gastroenteritis and colitis (K52.0) Gastroenteritis and colitis due to radiation (K52.1) Toxic gastroenteritis and colitis (K52.2) Allergic and dietetic gastroenteritis and colitis (K52.8) Other specified noninfective gastroenteritis and colitis (K52.9) Noninfective gastroenteritis and colitis, unspecified - (K52.0) Gastroenteritis and colitis due to radiation - (K52.1) Toxic gastroenteritis and colitis - (K52.2) Allergic and dietetic gastroenteritis and colitis - (K52.8) Other specified noninfective gastroenteritis and colitis - (K52.9) Noninfective gastroenteritis and colitis, unspecified ## (K55-K63) Other diseases of intestines - (K55) Vascular disorders of intestine (K55.0) Acute vascular disorders of intestine (K55.1) Chronic vascular disorders of intestine Mesenteric vascular insufficiency (K55.2) Angiodysplasia of colon (K55.8) Other vascular disorders of intestine (K55.9) Vascular disorder of intestine, unspecified - (K55.0) Acute vascular disorders of intestine - (K55.1) Chronic vascular disorders of intestine Mesenteric vascular insufficiency - Mesenteric vascular insufficiency - (K55.2) Angiodysplasia of colon - (K55.8) Other vascular disorders of intestine - (K55.9) Vascular disorder of intestine, unspecified - (K56) Paralytic ileus and intestinal obstruction without hernia (K56.0) Paralytic ileus (K56.1) Intussusception (K56.2) Volvulus (K56.3) Gallstone ileus (K56.4) Other impaction of intestine (K56.5) Intestinal adhesions (bands) with obstruction (K56.6) Other and unspecified intestinal obstruction (K56.7) Ileus, unspecified - (K56.0) Paralytic ileus - (K56.1) Intussusception - (K56.2) Volvulus - (K56.3) Gallstone ileus - (K56.4) Other impaction of intestine - (K56.5) Intestinal adhesions (bands) with obstruction - (K56.6) Other and unspecified intestinal obstruction - (K56.7) Ileus, unspecified - (K57) Diverticular disease of intestine (K57.0) Diverticular disease of small intestine with perforation and abscess (K57.1) Diverticular disease of small intestine without perforation or abscess (K57.2) Diverticular disease of large intestine with perforation and abscess (K57.3) Diverticular disease of large intestine without perforation or abscess (K57.4) Diverticular disease of both small and large intestine with perforation and abscess (K57.5) Diverticular disease of both small and large intestine without perforation or abscess (K57.8) Diverticular disease of intestine, part unspecified, with perforation and abscess (K57.9) Diverticular disease of intestine, part unspecified, without perforation or abscess - (K57.0) Diverticular disease of small intestine with perforation and abscess - (K57.1) Diverticular disease of small intestine without perforation or abscess - (K57.2) Diverticular disease of large intestine with perforation and abscess - (K57.3) Diverticular disease of large intestine without perforation or abscess - (K57.4) Diverticular disease of both small and large intestine with perforation and abscess - (K57.5) Diverticular disease of both small and large intestine without perforation or abscess - (K57.8) Diverticular disease of intestine, part unspecified, with perforation and abscess - (K57.9) Diverticular disease of intestine, part unspecified, without perforation or abscess - (K58) Irritable bowel syndrome - (K59) Other functional intestinal disorders (K59.0) Constipation (K59.1) Functional diarrhoea (K59.2) Neurogenic bowel, not elsewhere classified (K59.3) Megacolon, not elsewhere classified Toxic megacolon (K59.4) Anal spasm Proctalgia fugax (K59.8) Other specified functional intestinal disorders (K59.9) Functional intestinal disorder, unspecified - (K59.0) Constipation - (K59.1) Functional diarrhoea - (K59.2) Neurogenic bowel, not elsewhere classified - (K59.3) Megacolon, not elsewhere classified Toxic megacolon - Toxic megacolon - (K59.4) Anal spasm Proctalgia fugax - Proctalgia fugax - (K59.8) Other specified functional intestinal disorders - (K59.9) Functional intestinal disorder, unspecified - (K60) Fissure and fistula of anal and rectal regions (K60.0) Acute anal fissure (K60.1) Chronic anal fissure (K60.2) Anal fissure, unspecified (K60.3) Anal fistula (K60.4) Rectal fistula (K60.5) Anorectal fistula - (K60.0) Acute anal fissure - (K60.1) Chronic anal fissure - (K60.2) Anal fissure, unspecified - (K60.3) Anal fistula - (K60.4) Rectal fistula - (K60.5) Anorectal fistula - (K61) Abscess of anal and rectal regions (K61.0) Anal abscess - (K61.0) Anal abscess - (K62) Other diseases of anus and rectum (K62.0) Anal polyp (K62.1) Rectal polyp (K62.2) Anal prolapse (K62.3) Rectal prolapse (K62.4) Stenosis of anus and rectum (K62.5) Haemorrhage of anus and rectum (K62.6) Ulcer of anus and rectum (K62.7) Radiation proctitis (K62.8) Other specified diseases of anus and rectum Proctitis NOS (K62.9) Disease of anus and rectum, unspecified - (K62.0) Anal polyp - (K62.1) Rectal polyp - (K62.2) Anal prolapse - (K62.3) Rectal prolapse - (K62.4) Stenosis of anus and rectum - (K62.5) Haemorrhage of anus and rectum - (K62.6) Ulcer of anus and rectum - (K62.7) Radiation proctitis - (K62.8) Other specified diseases of anus and rectum Proctitis NOS - Proctitis NOS - (K62.9) Disease of anus and rectum, unspecified - (K63) Other diseases of intestine (K63.0) Abscess of intestine (K63.1) Perforation of intestine (nontraumatic) (K63.2) Fistula of intestine (K63.3) Ulcer of intestine (K63.4) Enteroptosis (K63.5) Polyp of colon (K63.8) Other specified diseases of intestine (K63.9) Disease of intestine, unspecified - (K63.0) Abscess of intestine - (K63.1) Perforation of intestine (nontraumatic) - (K63.2) Fistula of intestine - (K63.3) Ulcer of intestine - (K63.4) Enteroptosis - (K63.5) Polyp of colon - (K63.8) Other specified diseases of intestine - (K63.9) Disease of intestine, unspecified ## (K65-K67) Diseases of peritoneum - (K65) Peritonitis - (K66) Other disorders of peritoneum - (K67) Disorders of peritoneum in infectious diseases classified elsewhere ## (K70-K77) Diseases of liver - (K70) Alcoholic liver disease (K70.0) Alcoholic fatty liver (K70.1) Alcoholic hepatitis (K70.2) Alcoholic fibrosis and sclerosis of liver (K70.3) Alcoholic cirrhosis of liver (K70.4) Alcoholic hepatic failure (K70.9) Alcoholic liver disease, unspecified - (K70.0) Alcoholic fatty liver - (K70.1) Alcoholic hepatitis - (K70.2) Alcoholic fibrosis and sclerosis of liver - (K70.3) Alcoholic cirrhosis of liver - (K70.4) Alcoholic hepatic failure - (K70.9) Alcoholic liver disease, unspecified - (K71) Toxic liver disease (K71.0) Toxic liver disease with cholestasis (K71.1) Toxic liver disease with hepatic necrosis (K71.2) Toxic liver disease with acute hepatitis (K71.3) Toxic liver disease with chronic persistent hepatitis (K71.4) Toxic liver disease with chronic lobular hepatitis (K71.5) Toxic liver disease with chronic active hepatitis (K71.6) Toxic liver disease with hepatitis, not elsewhere classified (K71.7) Toxic liver disease with fibrosis and cirrhosis of liver (K71.8) Toxic liver disease with other disorders of liver (K71.9) Toxic liver disease, unspecified - (K71.0) Toxic liver disease with cholestasis - (K71.1) Toxic liver disease with hepatic necrosis - (K71.2) Toxic liver disease with acute hepatitis - (K71.3) Toxic liver disease with chronic persistent hepatitis - (K71.4) Toxic liver disease with chronic lobular hepatitis - (K71.5) Toxic liver disease with chronic active hepatitis - (K71.6) Toxic liver disease with hepatitis, not elsewhere classified - (K71.7) Toxic liver disease with fibrosis and cirrhosis of liver - (K71.8) Toxic liver disease with other disorders of liver - (K71.9) Toxic liver disease, unspecified - (K72) Hepatic failure, not elsewhere classified Hepatic encephalopathy - Hepatic encephalopathy - (K73) Chronic hepatitis, not elsewhere classified - (K74) Fibrosis and cirrhosis of liver (K74.0) Hepatic fibrosis (K74.1) Hepatic sclerosis (K74.2) Hepatic fibrosis with hepatic sclerosis (K74.3) Primary biliary cirrhosis (K74.4) Secondary biliary cirrhosis (K74.5) Biliary cirrhosis, unspecified (K74.6) Other and unspecified cirrhosis of liver - (K74.0) Hepatic fibrosis - (K74.1) Hepatic sclerosis - (K74.2) Hepatic fibrosis with hepatic sclerosis - (K74.3) Primary biliary cirrhosis - (K74.4) Secondary biliary cirrhosis - (K74.5) Biliary cirrhosis, unspecified - (K74.6) Other and unspecified cirrhosis of liver - (K75) Other inflammatory liver diseases (K75.0) Abscess of liver (K75.1) Phlebitis of portal vein (K75.2) Nonspecific reactive hepatitis (K75.3) Granulomatous hepatitis, not elsewhere classified (K75.4) Autoimmune hepatitis (K75.8) Other specified inflammatory liver diseases (K75.9) Inflammatory liver disease, unspecified Hepatitis NOS - (K75.0) Abscess of liver - (K75.1) Phlebitis of portal vein - (K75.2) Nonspecific reactive hepatitis - (K75.3) Granulomatous hepatitis, not elsewhere classified - (K75.4) Autoimmune hepatitis - (K75.8) Other specified inflammatory liver diseases - (K75.9) Inflammatory liver disease, unspecified Hepatitis NOS - Hepatitis NOS - (K76) Other diseases of liver (K76.0) Fatty (change of) liver, not elsewhere classified (K76.1) Chronic passive congestion of liver (K76.2) Central haemorrhagic necrosis of liver (K76.3) Infarction of liver (K76.4) Peliosis hepatis (K76.5) Hepatic veno-occlusive disease (K76.6) Portal hypertension (K76.7) Hepatorenal syndrome (K76.8) Other specified diseases of liver (K76.9) Liver disease, unspecified - (K76.0) Fatty (change of) liver, not elsewhere classified - (K76.1) Chronic passive congestion of liver - (K76.2) Central haemorrhagic necrosis of liver - (K76.3) Infarction of liver - (K76.4) Peliosis hepatis - (K76.5) Hepatic veno-occlusive disease - (K76.6) Portal hypertension - (K76.7) Hepatorenal syndrome - (K76.8) Other specified diseases of liver - (K76.9) Liver disease, unspecified - (K77) Liver disorders in diseases classified elsewhere ## (K80-K87) Disorders of gallbladder, biliary tract and pancreas - (K80) Cholelithiasis (K80.0) Calculus of gallbladder with acute cholecystitis (K80.1) Calculus of gallbladder with other cholecystitis (K80.2) Calculus of gallbladder without cholecystitis (K80.3) Calculus of bile duct with cholangitis (K80.4) Calculus of bile duct with cholecystitis (K80.5) Calculus of bile duct without cholangitis or cholecystitis Choledocholithiasis (K80.8) Other cholelithiasis - (K80.0) Calculus of gallbladder with acute cholecystitis - (K80.1) Calculus of gallbladder with other cholecystitis - (K80.2) Calculus of gallbladder without cholecystitis - (K80.3) Calculus of bile duct with cholangitis - (K80.4) Calculus of bile duct with cholecystitis - (K80.5) Calculus of bile duct without cholangitis or cholecystitis Choledocholithiasis - Choledocholithiasis - (K80.8) Other cholelithiasis - (K81) Cholecystitis - (K82) Other diseases of gallbladder (K82.0) Obstruction of gallbladder (K82.1) Hydrops of gallbladder (K82.2) Perforation of gallbladder (K82.3) Fistula of gallbladder (K82.4) Cholesterolosis of gallbladder Strawberry gallbladder (K82.8) Other specified diseases of gallbladder (K82.9) Disease of gallbladder, unspecified - (K82.0) Obstruction of gallbladder - (K82.1) Hydrops of gallbladder - (K82.2) Perforation of gallbladder - (K82.3) Fistula of gallbladder - (K82.4) Cholesterolosis of gallbladder Strawberry gallbladder - Strawberry gallbladder - (K82.8) Other specified diseases of gallbladder - (K82.9) Disease of gallbladder, unspecified - (K83) Other diseases of biliary tract (K83.0) Cholangitis (K83.1) Obstruction of bile duct (K83.2) Perforation of bile duct (K83.3) Fistula of bile duct (K83.4) Spasm of sphincter of Oddi (K83.5) Biliary cyst (K83.8) Other specified diseases of biliary tract (K83.9) Disease of biliary tract, unspecified - (K83.0) Cholangitis - (K83.1) Obstruction of bile duct - (K83.2) Perforation of bile duct - (K83.3) Fistula of bile duct - (K83.4) Spasm of sphincter of Oddi - (K83.5) Biliary cyst - (K83.8) Other specified diseases of biliary tract - (K83.9) Disease of biliary tract, unspecified - (K85) Acute pancreatitis - (K86) Other diseases of pancreas (K86.0) Alcohol-induced chronic pancreatitis (K86.1) Other chronic pancreatitis (K86.2) Cyst of pancreas (K86.3) Pseudocyst of pancreas (K86.8) Other specified diseases of pancreas (K86.9) Disease of pancreas, unspecified - (K86.0) Alcohol-induced chronic pancreatitis - (K86.1) Other chronic pancreatitis - (K86.2) Cyst of pancreas - (K86.3) Pseudocyst of pancreas - (K86.8) Other specified diseases of pancreas - (K86.9) Disease of pancreas, unspecified - (K87) Disorders of gallbladder, biliary tract and pancreas in diseases classified elsewhere ## (K90-K93) Other diseases of the digestive system - (K90) Intestinal malabsorption (K90.0) Coeliac disease (K90.1) Tropical sprue (K90.2) Blind loop syndrome, not elsewhere classified (K90.3) Pancreatic steatorrhoea (K90.4) Malabsorption due to intolerance, not elsewhere classified (K90.8) Other intestinal malabsorption (K90.9) Intestinal malabsorption, unspecified - (K90.0) Coeliac disease - (K90.1) Tropical sprue - (K90.2) Blind loop syndrome, not elsewhere classified - (K90.3) Pancreatic steatorrhoea - (K90.4) Malabsorption due to intolerance, not elsewhere classified - (K90.8) Other intestinal malabsorption - (K90.9) Intestinal malabsorption, unspecified - (K91) Postprocedural disorders of digestive system, not elsewhere classified (K91.0) Vomiting following gastrointestinal surgery (K91.1) Postgastric surgery syndromes dumping syndrome postgastrectomy syndrome postvagotomy syndrome (K91.2) Postsurgical malabsorption, not elsewhere classified (K91.3) Postoperative intestinal obstruction (K91.4) Colostomy and enterostomy malfunction (K91.5) Postcholecystectomy syndrome (K91.8) Other postprocedural disorders of digestive system, not elsewhere classified (K91.9) Postprocedural disorder of digestive system, unspecified - (K91.0) Vomiting following gastrointestinal surgery - (K91.1) Postgastric surgery syndromes dumping syndrome postgastrectomy syndrome postvagotomy syndrome - dumping syndrome - postgastrectomy syndrome - postvagotomy syndrome - (K91.2) Postsurgical malabsorption, not elsewhere classified - (K91.3) Postoperative intestinal obstruction - (K91.4) Colostomy and enterostomy malfunction - (K91.5) Postcholecystectomy syndrome - (K91.8) Other postprocedural disorders of digestive system, not elsewhere classified - (K91.9) Postprocedural disorder of digestive system, unspecified - (K92) Other diseases of digestive system (K92.0) Haematemesis (K92.1) Melaena (K92.2) Gastrointestinal haemorrhage, unspecified (K92.8) Other specified diseases of digestive system (K92.9) Disease of digestive system, unspecified - (K92.0) Haematemesis - (K92.1) Melaena - (K92.2) Gastrointestinal haemorrhage, unspecified - (K92.8) Other specified diseases of digestive system - (K92.9) Disease of digestive system, unspecified - (K93) Disorders of other digestive organs in diseases classified elsewhere

Insertion of an annular disc implant at lumbar discectomy # Recommendations Current evidence on the safety and efficacy of insertion of an annular disc implant at lumbar discectomy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake insertion of an annular disc implant at lumbar discectomy should take the following actions: Inform the clinical governance leads in their NHS trusts. Ensure that patients and their carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. NICE encourages further research on insertion of an annular disc implant at lumbar discectomy, particularly comparative trials. All studies should report details of patient selection and recurrence rates. Clinicians should enter details about all patients undergoing insertion of an annular disc implant at lumbar discectomy onto the British Spine Registry and review clinical outcomes locally.# Indications and current treatments Lumbar disc herniation occurs when the nucleus pulposus of an intervertebral disc protrudes through a tear in the surrounding annulus fibrosus. Symptoms include pain in the back or leg, and numbness or weakness in the leg. Serious neurological sequelae may sometimes occur. Conservative treatments include analgesics, non‑steroidal anti‑inflammatory medication and physical therapy. Epidural corticosteroid injections can also be used to reduce nerve pain in the short term. Lumbar discectomy is considered if there is evidence of severe nerve compression or persistent symptoms that are unresponsive to conservative treatment. Surgical techniques include open discectomy or minimally invasive alternatives using percutaneous approaches. Lumbar discectomy usually leaves a hole in the annulus fibrosus through which the nucleus herniated, which may lead to reherniation and progressive loss in disc height.# The procedure Insertion of an annular disc implant at lumbar discectomy aims to reduce the incidence of recurrent herniation and the degree of intervertebral disc collapse. With the patient under general anaesthesia, the herniated disc material is removed and the annular disc device is implanted. The device typically contains a metallic bone‑anchoring component and a woven polymer mesh. The bone‑anchoring component is inserted using a mallet and tamp into one of the vertebral bodies adjacent to the discectomy site, and the woven mesh component is inserted into the annular disc defect, so covering the residual nucleus pulposus. Fluoroscopy may be used to guide the procedure.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. A non‑randomised comparative study of 102 patients (30 patients treated by discectomy plus annular disc implant and 72 patients treated by discectomy only) reported no reherniations in the implant group within 2 years after surgery and 5 reherniations in the discectomy‑only group: 3% (2/72) within 3 months and 4% (3/72) between 4 months and 2 years after surgery (level of significance not stated). A non‑randomised comparative cohort study of 76 patients (30 patients from the same implant cohort as in the previous study and 46 patients treated by discectomy only) reported no reherniations 2 years after surgery in the implant group and 7% (3/46) in the discectomy‑only group (no significant difference). The non‑randomised comparative study of 102 patients reported improvement in Oswestry Disability Index (ODI) scores in both groups. In the implant group, the ODI score decreased from 62.7 before surgery to 31.4 after 6 weeks and 11.6 after 24 months. In the discectomy‑only group, the ODI score decreased from 49.4 before surgery to 30.7 after 6 weeks and 19.8 after 24 months. The scores were significantly different between the 2 groups at baseline (before surgery) (p=0.0004) but not at 6 weeks and 24 months. The non‑randomised comparative study of 102 patients reported that back pain scores and leg pain scores (both measured on 100‑point visual analogue scales, with higher scores indicating more severe pain) improved in both groups. Back pain scores improved from 66.3 before surgery to 10.5 after 24 months in the implant group and from 43.1 to 19.1 in the discectomy‑only group (level of significance not stated). Leg pain scores improved from 79.8 before surgery to 8.9 after 24 months in the implant group and from 58.8 to 21.2 in the discectomy‑only group (level of significance not stated). The scores for back and leg pain were significantly different between the 2 groups at baseline (before surgery; p≤0.0001). The scores for leg pain (but not for back pain) were significantly different between the 2 groups at 12 months and 24 months (p<0.05). The non‑randomised comparative cohort study of 76 patients reported a mean loss of disc height from 8.60 mm to 7.63 mm (0.97 mm loss) in the implant group compared with 8.30 mm to 6.90 mm (1.40 mm loss) in the discectomy‑only group 12 months after surgery (p=0.054). A case series of 45 patients reported a decrease of the mean disc height to 93% of baseline 12 months after surgery (p<0.01). The specialist advisers identified a key efficacy outcome as recurrence of herniation in the long term.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. Incidental durotomy (potentially causing cerebrospinal fluid leakage and complications such as headache) occurring during disc fragment removal was reported in 1 patient treated by discectomy plus annular disc implantation and in 1 patient treated by discectomy only in a non‑randomised comparative study of 102 patients (30 patients treated by discectomy plus annular disc implant and 72 patients treated by discectomy only; level of significance not stated). Incidental durotomy was reported in 1 patient treated by discectomy plus annular disc implantation and in 1 patient treated by discectomy only in a non‑randomised comparative cohort study of 76 patients (30 patients from the same implant cohort as in the previous study and 46 patients treated by discectomy only; level of significance not stated). Suspected discitis 56 days after surgery was reported in 1 patient treated by discectomy plus annular disc implantation and in none of the patients treated by discectomy only in the non‑randomised comparative cohort study of 76 patients (level of significance not stated). The infection was successfully treated by intravenous antibiotics. Reoperations were reported in 3 patients treated by annular disc implantation after discectomy in a case series of 45 patients: 1 was a symptomatic reherniation 4 months after surgery because the device was implanted too deep into the disc space, 1 was a contralateral herniation 3 weeks after surgery possibly caused by the implant, and 1 was for excessive scar tissue 5 months after surgery. The specialist advisers listed additional theoretical adverse events as haematoma, cauda equina damage, implant displacement causing nerve root damage, pain, numbness, weakness and neurological compression.# Further information For related NICE guidance, see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.

Metre per second Metre per second (U.S. spelling: meter per second) is an SI derived unit of both speed (scalar) and velocity (vector quantity which specifies both magnitude and a specific direction), defined by distance in metres divided by time in seconds. The official SI symbolic abbreviation is m·s−1, or equivalently, m/s; although the abbreviation mps is sometimes used colloquially. Where metres per second are several orders of magnitude too slow to be convenient, such as in astronomical measurements, velocities may be given in terms of kilometres per second, where 1 km/s is equivalent to 1,000 metres per second; in popular, non-science literature kps is occasionally used instead of km/s. One metre per second is roughly the speed of an average person walking. # Conversions 1 metre per second is equivalent to: 1 foot per second = 0.3048 m·s−1 (exactly) 1 mile per hour ≈ 0.4471 m·s−1 (approximately) 1 km·h-1 ≈ 0.2778 m·s−1 (approximately) 1 kilometre per second is equivalent to: # Remark Although m·s−1 is an SI derived unit, it could be viewed as more fundamental than the metre, since the latter is derived from the speed of light in a vacuum, which is defined as exactly 299 792 458 m·s−1. It follows that one metre is the length of the path travelled by light in a vacuum during a time interval of 1/299 792 458 of one second.

Pseudoephedrine Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. Pseudoephedrine (commonly abbreviated as PSE) is a sympathomimetic amine commonly used as a decongestant. The salts pseudoephedrine hydrochloride and pseudoephedrine sulfate are found in many over-the-counter preparations either as single-ingredient preparations, or more commonly in combination with antihistamines, paracetamol and/or ibuprofen. Consumers in North America, the United Kingdom, and Australia often refer to it as Sudafed, the trademark for a common brand of pseudoephedrine hydrochloride, although Pfizer now sells products without pseudoephedrine under the brand name (as Sudafed PE). Unlike antihistamines, which modify the systemic histamine-mediated allergic response, pseudoephedrine only relieves nasal congestion commonly associated with colds or allergies. However, some users report rapid and effective relief from other allergic symptoms, including itchy and/or watery eyes, which may not have been provided effectively by antihistamines. The advantage of oral pseudoephedrine over topical nasal preparations, such as oxymetazoline, is that it does not cause rebound congestion (rhinitis medicamentosa); however, it is more likely to cause adverse effects including hypertension. # Chemistry Pseudoephedrine is a phenethylamine, and a diastereomer of ephedrine. Pseudoephedrine is a chiral molecule, meaning it occurs in both "left-handed" and "right-handed" configurations which are not superimposable. Pseudoephedrine is the International Nonproprietary Name (INN) of the (1S,2S)- diastereomer of ephedrine (which has 1R,2S- configuration). Other names are (+)-pseudoephedrine and D-pseudoephedrine (Reynolds, 1989). L-Pseudoephedrine, also known as (-)-(1R,2R)-pseudoephedrine or (-)-pseudoephedrine, is the optical isomer of D-pseudoephedrine. It has fewer side-effects, fewer central nervous system (CNS) stimulatory effects, does not reduce to D-methamphetamine (which is the enatiomer used as a recreational drug), and yet it retains its efficacy as a decongestant. However, the patent holder for L-pseudoephedrine (Pfizer/Warner-Lambert) has not yet sought or received government approval for its sale to the public. (U.S. Patent 6,495,529) # Mode of action Pseudoephedrine is a sympathomimetic amine — that is, its principal mechanism of action relies on its indirect action on the adrenergic receptor system. While it may have weak agonist activity at α- and β-adrenergic receptors, the principal mechanism is to displace noradrenaline from storage vesicles in presynaptic neurons. The displaced noradrenaline is released into the neuronal synapse where it is free to activate the aforementioned postsynaptic adrenergic receptors. These adrenergic receptors are located on the muscles lining the walls of blood vessels. When activiated by pseudoephedrine, the muscles contract, causing the blood vessels to constrict (vasoconstriction). These constricted blood vessels now allow less fluid to leave the blood vessels and enter the nose, throat and sinus linings, which results in decreased inflammation of nasal membranes as well as decreased mucous production. Thus, by constriction of blood vessels, mainly those located in the nasal passages, pseudoephedrine causes a decrease in the symptoms of nasal congestion. The vasoconstriction that pseudoephedrine produces is believed to be principally an α-adrenergic receptor response. While all sympathomimetic amines, to some extent, have decongestant action, pseudoephedrine shows greater selectivity for the nasal mucosa and a lower affinity for central nervous system (CNS) adrenergic-receptors than other sympathomimetic amines. Vasoconstriction in the nasal mucosa shrinks swollen nasal mucous membranes, reduces tissue hyperaemia, oedema, and nasal congestion. Other beneficial effects may include increasing the drainage of sinus secretions, and opening of obstructed Eustachian tubes. The same vasoconstriction action can also result in hypertension, which is a noted side effect of pseudoephedrine. # Clinical use ## Indications Pseudoephedrine is indicated for the treatment of: - Nasal congestion - Sinus congestion - Eustachian tube congestion. (Bicopoulos, 2002) Pseudoephedrine is also indicated for vasomotor rhinitis, and as an adjunct to other agents in the optimum treatment of allergic rhinitis, croup, sinusitis, otitis media, and tracheobronchitis. (Bicopoulos, 2002) Pseudoephedrine is also used as first-line therapy of priapism. Erection is largely a parasympathetic response, so the sympathetic action of pseudoephedrine may serve to relieve this condition. Treatment for urinary incontinence is an unlabeled use for these medications. Unlabeled use means doctors can use the medication to treat a condition other than that for which it was first approved by the U.S. Food and Drug Administration (FDA). These medications are approved by the FDA for the treatment of nasal congestion caused by colds or allergies. However it has also been successful in treating stress incontinence by increasing the pressure (tension) exerted by the muscles of the bladder neck and the urethra, which helps retain the urine within the bladder. ## Adverse effects Common adverse drug reactions (ADRs) associated with pseudoephedrine therapy include: CNS stimulation, sleeplessness, nervousness, excitability, dizziness and anxiety. Infrequent ADRs include: tachycardia and/or palpitations. Rarely, pseudoephedrine therapy may be associated with hallucinations, arrhythmias, hypertension, seizures and ischemic colitis (Rossi, 2006); as well as severe skin reactions known as recurrent pseudo-scarlatina, systemic contact dermatitis, and nonpigmenting fixed drug eruption (Vidal, Prieto, Peréz-Carral, Armisén 1998). It has also been reported that pseudoephedrine, amongst other sympathomimetic agents, may be associated with the occurrence of stroke (Cantu et al., 2003). ## Precautions and contraindications Pseudoephedrine should be used with caution in patients with: diabetes mellitus, cardiovascular disease, hypertension, prostatic hypertrophy, hyperthyroidism, closed angle glaucoma and/or pregnancy (Rossi, 2006). Since nasal congestion is considered to be a relatively minor ailment, alternatives are preferred in patients with these conditions. Appropriate alternatives may include topical decongestants or saline sprays/instillations, depending on the patient's condition. Contraindications for the use of pseudoephedrine include: concomitant or recent (previous fourteen days) monoamine oxidase inhibitor (MAOI) therapy, severe or uncontrolled hypertension, and/or severe coronary artery disease (Rossi, 2006). People with bipolar disorder should use care when taking pseudoephedrine, as it can cause insomnia and thus trigger a manic episode. # Chiral auxiliary Both (R,R)- and (S,S)-pseudoephedrine are used as a chiral auxiliary. Pseudoephedrine is reacted with a carboxylic acid, acid anhydride, or acyl chloride to give a pseudoephedrine amide. The α-proton of the carbonyl compound is easily deprotonated by a non-nucleophilic base to give the enolate, which can further react. The configuration of the addition compound, such as with an alkyl halide, is directed by the methyl group. Thus, any addition product will be anti to the methyl and syn with the hydroxyl group. The pseudoephedrine chiral auxiliary is subsequently removed by cleaving the amide bond with an appropriate nucleophile. # Manufacture Although pseudoephedrine occurs naturally as an alkaloid in certain plant species (for example, as a constituent of extracts from the ephedra species, also known as Ma Huang, in which it occurs together with other isomers of ephedrine), the majority of pseudoephedrine produced for commercial use is derived from yeast fermentation of dextrose in the presence of benzaldehyde. In this process, specialized strains of yeast (typically a variety of Candida utilis or Saccharomyces cerevisiae) are added to large vats containing water, dextrose and the enzyme pyruvate decarboxylase (such as found in beets and other plants). After the yeast has begun fermenting the dextrose, the benzaldehyde is added to the vats, and in this environment the yeast convert the precursor ingredients to l-phenylacetylcarbinol (L-PAC). L-PAC is then chemically converted to pseudoephedrine via reductive amination (Oliver, 1999). The bulk of pseudoephedrine is produced by commercial pharmaceutical manufacturers in India and China, where economic and industrial conditions favor the mass production of pseudoephedrine for export (Suo, 2004). # Misuse and illicit use There have also been reports of off-label uses of pseudoephedrine for its stimulant properties. Some patients, long-distance truck drivers and sports athletes for example, have reportedly used pseudoephedrine as a stimulant to increase their state of alertness/awakedness. It is doubtful that pseudoephedrine would be of significant benefit, except in sensitive individuals, because of its minimal effect in the central nervous system (see Mode of Action above). Nevertheless, such misuse of pseudoephedrine has been associated with stimulant dependence. The similarity in chemical structure to the amphetamines has made pseudoephedrine a sought-after chemical precursor in the illicit manufacture of methamphetamine and methcathinone. As a result of the increasing regulatory restrictions on the sale and distribution of pseudoephedrine, many pharmaceutical firms have reformulated, or are in the process of reformulating medications to use alternative decongestants, such as phenylephrine. Many retailers such as Target, Wal-Mart, CVS, and Winn-Dixie have created corporate policies restricting the sale of pseudoephedrine-containing products. Their policies restrict sales by limiting purchase quantities and requiring a minimum age with proper identification. These requirements are similar to and sometimes more stringent than existing law. Internationally, pseudoephedrine is listed as a Table I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances. ## United States federal law The United States Congress has recognized the use of pseudoephedrine in the illicit manufacture of methamphetamine. In late 2005, the Committee on Education and the Workforce heard testimony concerning education programs and state legislation designed to curb the use and manufacture of methamphetamine with pseudoephedrine-containing products. State laws in Oregon and Kansas were particularly influential in the proposed legislation. The House passed the Combat Methamphetamine Epidemic Act of 2005 ("CMEA") as an amendment to the renewal of the Patriot Act. Signed into law by president George W. Bush on March 6, 2006, the act amended the US Code (21 USC 830) concerning the sale of pseudoephedrine containing products. The Federal statute included the following requirements for merchants ("regulated seller") who sell these products (pseudoephedrine is defined as a "scheduled listed chemical product under 21 USC 802(45(A)): - A retrievable record of all purchases identifying the name and address of each party to be kept for two years. - Required verification of proof of identity of all purchasers - Required protection and disclosure methods in the collection of personal information - Reports to the Attorney General of any suspicious payments or disappearances of the regulated products - Required training of employees with regard to the requirements of the CMEA; Retailer must self-certify as to training and compliance - Non-liquid dose form of regulated product may only be sold in unit dose blister packs - Regulated products are to be sold behind the counter or in a locked cabinet in such a way as to restrict public access - Daily sales of regulated products not to exceed 3.6 grams without regard to the number of transactions - 30 day (not monthly) sales limit not to exceed 7.5 grams if sold by mail-order or "mobile retail vendor" - 30 day PURCHASE limit not to exceed 9 grams of pseudoephedrine base in regulated products (misdemeanor possession offense under 21 USC 844a for the individual who buys it) ## United States state law Individual states also have varying laws on the matter, e.g. Alabama, Arizona, California, Connecticut, Colorado, Delaware, Georgia, Florida, Illinois, Indiana, Iowa, Kansas, Massachusetts, Maryland, Michigan, Minnesota, Missouri, Montana, New Jersey, New York, North Carolina, Oklahoma, Pennsylvania, Rhode Island, Tennessee, Texas, Utah, Vermont, Virginia, and Washington laws require pharmacies to sell pseudoephedrine behind-the-counter and to collect personal information from the purchaser. As of July 1 2006, Oregon recognizes pseudoephedrine and all pseudoephedrine containing products as a Schedule III controlled substance, and requires a prescription to purchase them. ## Australia Illicit diversion of pseudoephedrine in Australia has caused significant changes to the way pseudoephedrine products are regulated. As of 2006, all products containing pseudoephedrine have been rescheduled as "Pharmacist Only Medicines" (Schedule 3). As a result, a pharmacist must be directly involved in every transaction involving the sale of pseudoephedrine to members of the public, and such medicines will be kept behind the counter, away from public access. Such measures are designed to ensure that the medicines are needed for a legitimate purpose. Pharmacists are also required lodge the purchase with an online database called PROJECTSTOP. This database records each purchase of pseudoephedrine products, tracking the customers drivers license or 18+ card. This system was put in place to stop drug mules driving from Sydney to Cairns (a trip of 3000km or 1875mi) purchasing a small box of pseudoephedrine at every pharmacy along the way. When the database is used 3 modes of sale can be used. One allows the sale (as "no match" was found), one denies the sale and the third, called a safety sale, is when the product was sold under duress. Certain preparations containing significantly high amounts of pseudoephedrine are further restricted as "Prescription Only Medicines" (Schedule 4). As of April 2007, the Australian government is considering the prohibition of all medications containing pseudoephedrine. ## New Zealand In New Zealand, from 15 October 2004, as a result of large intercepts of pseudoephedrine and ephedrine, any product containing these substances e.g. cold and flu medicines were classified as Class C controlled drugs in the Misuse of Drugs Act 1975. New Zealand Customs and police officers are continuing to make large interceptions of precursor substances believed to be destined for methamphetamine production. # Brand names - Contac (pseudoephedrine) - Has been discontinued as of 2007 - Codral (pseudoephedrine HCI) - Sudafed (pseudoephedrine) - has an alternate phenylephrine HCl version, Sudafed PE - Actifed (triprolidine/pseudoephedrine) - no longer contains pseudoephedrine as of 2007 - Claritin-D (loratadine/pseudoephedrine) - Clarinex-D (desloratadine/pseudoephedrine) - Sinutab (Paracetamol/pseudoephedrine) - Sinufed (pseudoephedrine HCI) - Benylin (pseudoephedrine) - Zyrtec-D (certirizine/pseudoephedrine) - Prescription only - Allegra-D (fexofenadine/pseudoephedrine) - Prescription only - Drixoral (dexbrompheniramine/pseudoephedrine) - Mucinex-D (guaifenesin/pseudoephedrine) - PediaCare (pseudoephedrine/chlorpheniramine/dextromethorphan) - Pannaz (pseudoephedrine/chlorpheniramine/methscopolamine) - Fludrex (pseudoephedrine/dextromethorphan/triprolidine) - Solpa-Sinus (pseudoephedrine/acetaminophen) - Advil Cold and Sinus (pseudoephedrine/ibuprofen) - Tylenol Sinus (pseudoephedrine/acetaminophen)

Scattered disk radiation astronomy Scattered Disk Objects (up to 100 AU): Kuiper Belt objects are shown in grey, resonant objects within the Scattered Disk are shown in green. The position of an object represents - its orbit’s semi-major axis a in AU and the orbital period in years (horizontal axis) - its orbit’s inclination i in degrees (vertical axis). The size of the circle illustrates the object’s size relative to others. For a few large objects, the diameter drawn represents the best current estimates. For all others, the circles represent the absolute magnitude of the object. The eccentricity of the orbit is shown indirectly by a segment extending from the left (perihelion) to the aphelion to the right. In other words, the segment illustrates the variations of the object's distance from the Sun. Objects with nearly circular orbits will show short segments while highly elliptical orbits will be represented by long segments. Main resonances with Neptune are marked with vertical bars; 1:1 marks the position of Neptune’s orbit (and its Trojan asteroids), 2:3 marks the orbit of Pluto (and plutinos) etc. The scattered disc (or scattered disk) is a distant region of the Solar System that is sparsely populated by icy minor planets, a subset of the broader family of trans-Neptunian objects. The scattered-disc objects (SDOs) have orbital eccentricities ranging as high as 0.8, inclinations as high as 40°, and perihelia greater than 30 astronomical units (4.5 x 109 km; 2.8 x 109 mi.). While the nearest distance to the Sun approached by scattered objects is about 30–35 AU, their orbits can extend well beyond 100 AU. This makes scattered objects "among the most distant and cold objects in the Solar System". The innermost portion of the scattered disc overlaps with a torus-shaped region of orbiting objects traditionally called the Kuiper belt, but its outer limits reach much farther away from the Sun and farther above and below the ecliptic than the Kuiper belt proper. The literature is inconsistent in the use of the phrases "scattered disc" and "Kuiper belt"; for some, they are distinct populations; for others, the scattered disc is part of the Kuiper belt and authors may even switch between these two uses in a single publication. # Periodic comets The image at the right is an optical astronomy image of the comet 67P/Churyumov-Gerasimenko. Rosetta's OSIRIS narrow-angle camera made the image on 3 August 2014 from a distance of 285 km. The image resolution is 5.3 metres/pixel. The left image is rotated 90° from the right. The location of the right image is the front view of the left side just out of view in the left image. The object rotates by the right hand rule from the left image to the right. Note that due to the evaporation of volatiles, the surface of the rocky object appears pitted or cratered. Def. a "comet which orbits the Sun and which returns to the innermost point of its orbit at known, regular intervals" is called a periodic comet. "The short period comets have orbital periods <20 years and low inclination. Their orbits are controlled by Jupiter and thus they are also called Jupiter Family comets. Because the orbit crosses that of Jupiter, the comet will have gravitational interactions with this massive planet. The objects orbit will gradually change from these interactions and eventually the object will either be thrown out of the Solar System or collide with a planet or the Sun." Perihleion distance in AU = 1.243, eccentricity = 0.641, inclination = 7.0, and orbital period in years = 2.745. Because of its unstable nature, astronomers now consider the scattered disc to be the place of origin for most periodic comets in the Solar System, with the centaurs, a population of icy bodies between Jupiter and Neptune, being the intermediate stage in an object's migration from the disc to the inner Solar System. # Centaurs Def. an "icy planetoid that orbits the Sun between Jupiter and Neptune" is called a Centaur. "The recent investigation of the orbital distribution of Centaurs (Emel’yanenko et al., 2005) showed that there are two dynamically distinct classes of Centaurs, a dominant group with semimajor axes a > 60 AU and a minority group with a < 60 AU." "he intrinsic number of such objects is roughly an order of magnitude greater than that for a<60 AU". Centaurs are small Solar System bodies with a semi-major axis between those of the outer planets, generally have unstable orbits because they cross or have crossed the orbits of one or more of the giant planets; almost all their orbits have dynamic lifetimes of only a few million years. There is one centaur, 514107 Kaʻepaokaʻawela, which may be in a stable (though retrograde) orbit. Centaurs typically behave with characteristics of both asteroids and comets and are named after the mythological centaurs that were a mixture of horse and human. It has been estimated that there are around 44,000 centaurs in the Solar System with diameters larger than 1 kilometer. No centaur has been photographed up close, although there is evidence that Saturn's moon Phoebe, imaged by the Cassini–Huygens (Cassini) probe in 2004, may be a captured centaur that originated in the Kuiper belt. Even centaurs such as 2000 GM137 and 2001 XZ255}, which do not currently cross the orbit of any planet, are in gradually changing orbits that will be perturbed until they start to cross the orbit of one or more of the giant planets. The Minor Planet Center (MPC) defines centaurs as having a perihelion beyond the orbit of Jupiter (q > 5.2 AU) and a semi-major axis less than that of Neptune (a < 30.1 AU). The Jet Propulsion Laboratory (JPL) similarly defines centaurs as having a semi-major axis, a, between those of Jupiter (5.5 AU < a) and Neptune (a < 30.1 AU). The Deep Ecliptic Survey (DES) defines centaurs using a dynamical classification scheme. These classifications are based on the simulated change in behavior of the present orbit when extended over 10 million years. The DES defines centaurs as non-resonant objects whose instantaneous (osculating) perihelia are less than the osculating semi-major axis of Neptune at any time during the simulation. This definition is intended to be synonymous with planet-crossing orbits and to suggest comparatively short lifetimes in the current orbit. The collection The Solar System Beyond Neptune (2008) defines objects with a semi-major axis between those of Jupiter and Neptune and a Jupiter – Tisserand's parameter above 3.05 – as centaurs, classifying the objects with a Jupiter Tisserand's parameter below this and, to exclude Kuiper belt objects, an arbitrary perihelion cut-off half-way to Saturn (q < 7.35 AU) as Jupiter-family comets (This would make 60558 Echeclus (q = 5.8 AU, TJ = 3.03) and 52872 Okyrhoe (q = 5.8 AU; TJ = 2.95), which have traditionally been classified as centaurs, and 944 Hidalgo (q = 1.95 AU; TJ = 2.07), which has traditionally been considered an asteroid and is classified as a centaur by JPL, Jupiter-family comets, not centaurs.) and classifying those objects on unstable orbits with a semi-major axis larger than Neptune's as members of the scattered disc. Centaurs are objects that are non-resonant with a perihelion inside the orbit of Neptune that can be shown to likely cross the Hill sphere of a gas giant within the next 10 million years, so that centaurs can be thought of as objects scattered inwards and that interact more strongly and scatter more quickly than typical scattered-disc objects. The JPL Small-Body Database lists 452 centaurs. There are an additional 116 trans-Neptunian objects (objects with a semi-major axis further than Neptune's, i.e. a > 30.1 AU) with a perihelion closer than the orbit of Uranus (q < 19.2 AU). The Committee on Small Body Nomenclature of the International Astronomical Union has adopted the following naming convention for such objects: Befitting their centaur-like transitional orbits between TNOs and comets, "objects on unstable, non-resonant, giant-planet-crossing orbits with semimajor axes greater than Neptune's" are to be named for other hybrid and shape-shifting mythical creatures. Thus far, only the binary objects 65489 Ceto and Phorcys and 42355 Typhon and Echidna have been named according to the new policy. Centaurs with measured diameters listed as possible dwarf planets include 10199 Chariklo, (523727) 2014 NW65, 2060 Chiron, and 54598 Bienor. The colours of centaurs are very diverse, which challenges any simple model of surface composition. In the side-diagram, the colour indices are measures of apparent magnitude of an object through blue (B), visible (V) (i.e. green-yellow) and red (R) filters. The diagram illustrates these differences (in exaggerated colours) for all centaurs with known colour indices. For reference, two moons: Triton and Phoebe, and planet Mars are plotted (yellow labels, size not to scale). Centaurs appear to be grouped into two classes: - very red – for example 5145 Pholus - blue (or blue-grey, according to some authors) – for example 2060 Chiron # Trans-Neptunian objects Over a thousand trans-Neptunian objects were detected between 1992 and 2006. As of October 2018, the catalog of minor planets contains 528 numbered and more than 2,000 unnumbered TNOs. Twelve minor planets with a semi-major axis greater than 150 AU and perihelion greater than 30 AU are known, which are called extreme trans-Neptunian objects (ETNOs). Discrepancies in the early 1900s between the observed and expected orbits of Uranus and Neptune suggested that there were one or more additional planets beyond Neptune, but revised estimates of Neptune's mass from the Voyager 2 flyby in 1989 showed that the problem was spurious. While the relatively dimmer bodies, as well as the population as the whole, are reddish (V−I = 0.3–0.6), the bigger objects are often more neutral in colour (infrared index V−I < 0.2). This distinction leads to suggestion that the surface of the largest bodies is covered with ices, hiding the redder, darker areas underneath. # Pluto Pluto is the second largest dwarf planet known (after Eris]. In the image on the right are shown from left to right: Pluto, Charon, Nix and Hydra. The observations on the left by Hubble were made with the European Space Agency's Faint Object Camera. Pluto is a very peculiar object. Its orbit is tilted and is more elliptical than the orbits of any of the other planets in the solar system. Pluto also rotates upside down with its North Pole below the plane of the solar system in the opposite sense of the Earth and most of the other planets. Pluto is smaller than our own Moon and also denser than any of its neighbors in the outer solar system. Pluto is currently near its closest approach to the Earth in its 249 year journey around the Sun, and is approximately four and a half billion kilometers away. The bright object at the center of the frame is Pluto while Charon is the fainter object in the lower left. Charon is fainter than Pluto because it is smaller and, probably, because its surface is covered by water ice whereas Pluto is thought to be covered mainly by the more reflective methane frost or snow. As indicated in the diagram at the bottom of the photograph, Charon's orbit around Pluto is a circle seen nearly edge on from Earth, with a radius of almost twenty thousand kilometers - a distance equal to approximately one and a half times the diameter of the Earth. At the time of observation, Charon was near its maximum apparent distance from Pluto, so that its angular separation was about nine tenths of an arcsecond. Because of the peculiar orientation of the Pluto-Charon orbit with respect to our line of sight, Charon approaches to within less than one tenth of an arcsecond of Pluto every three days. "Over the weekend, scientists discovered that it is a bit bigger than they expected. Previous estimates had put it somewhere between 715 and 746 miles, but new information suggests Pluto's radius is about 736 miles across, putting it solidly at the upper end of the estimate." "At heights of about 11,000 feet, the Norgay Montes most closely approximates the height of the Rockies." "NASA scientists identified this newfound range of water-ice mountains based on high-res images obtained by the New Horizons spacecraft." "The mountain range is located in the dwarf planet's heart-shaped feature, called Tombaugh Regio after Pluto's discoverer, Clyde Tombaugh. The mountains rise to about the height of the Appalachian Mountains on Earth, which reach a maximum height of about 6,000 feet." In the latest data from NASA's New Horizons spacecraft, a new close-up image of Pluto reveals a vast, craterless plain that appears to be no more than 100 million years old, and is possibly still being shaped by geologic processes. This frozen region is north of Pluto's icy mountains, in the center-left of the heart feature, informally named "Tombaugh Regio" (Tombaugh Region). This fascinating icy plains region -- resembling frozen mud cracks on Earth -- has been informally named "Sputnik Planum" (Sputnik Plain) after the Earth's first artificial satellite. It has a broken surface of irregularly-shaped segments, roughly 12 miles (20 kilometers) across, bordered by what appear to be shallow troughs. Some of these troughs have darker material within them, while others are traced by clumps of hills that appear to rise above the surrounding terrain. Elsewhere, the surface appears to be etched by fields of small pits that may have formed by a process called sublimation, in which ice turns directly from solid to gas, just as dry ice does on Earth. The irregular shapes may be the result of the contraction of surface materials, similar to what happens when mud dries. Alternatively, they may be a product of convection, similar to wax rising in a lava lamp. On Pluto, convection would occur within a surface layer of frozen carbon monoxide, methane and nitrogen, driven by the scant warmth of Pluto's interior. Pluto's icy plains also display dark streaks that are a few miles long. These streaks appear to be aligned in the same direction and may have been produced by winds blowing across the frozen surface. The names, listed below, pay homage to the underworld mythology, pioneering space missions, historic pioneers who crossed new horizons in exploration, and scientists and engineers associated with Pluto and the Kuiper Belt. - Tombaugh Regio honors Clyde Tombaugh (1906–1997), the U.S. astronomer who discovered Pluto in 1930 from Lowell Observatory in Arizona. - Burney crater honors Venetia Burney (1918–2009), who as an 11-year-old schoolgirl suggested the name "Pluto" for Clyde Tombaugh's newly discovered planet. Later in life she taught mathematics and economics. - Sputnik Planitia is a large plain named for Sputnik 1, the first space satellite, launched by the Soviet Union in 1957. - Tenzing Montes and Hillary Montes are mountain ranges honoring Tenzing Norgay (1914–1986) and Sir Edmund Hillary (1919–2008), the Indian/Nepali Sherpa and New Zealand mountaineer were the first to reach the summit of Mount Everest and return safely. - Al-Idrisi Montes honors Ash-Sharif al-Idrisi (1100–1165/66), a noted Arab mapmaker and geographer whose landmark work of medieval geography is sometimes translated as "The Pleasure of Him Who Longs to Cross the Horizons." - Djanggawul Fossae defines a network of long, narrow depressions named for the Djanggawuls, three ancestral beings in indigenous Australian mythology who traveled between the island of the dead and Australia, creating the landscape and filling it with vegetation. - Sleipnir Fossa is named for the powerful, eight-legged horse of Norse mythology that carried the god Odin into the underworld. - Virgil Fossae honors Virgil, one of the greatest Roman poets and Dante's fictional guide through hell and purgatory in the Divine Comedy. - Adlivun Cavus is a deep depression named for Adlivun, the underworld in Inuit mythology. - Hayabusa Terra is a large land mass saluting the Japanese spacecraft and mission (2003–2010) that performed the first asteroid sample return. - Voyager Terra honors the pair of NASA spacecraft, launched in 1977, that performed the first "grand tour" of all four giant planets. The Voyager spacecraft are now probing the boundary between the Sun and interstellar space. - Tartarus Dorsa is a ridge named for Tartarus, the deepest, darkest pit of the underworld in Greek mythology. - Elliot crater recognizes James Elliot (1943–2011), an MIT researcher who pioneered the use of stellar occultations to study the solar system – leading to discoveries such as the rings of Uranus and the first detection of Pluto's thin atmosphere. # Charon On 22 June 1978, an astronomer at the U.S. Naval Observatory in Washington, D.C. was making routine measurements of photographic plates taken with the 1.55-meter (61-inch) Kaj Strand Astrometric Reflector at the USNO Flagstaff Station in Arizona. The purpose of these images was to refine the orbit of the far-flung planet Pluto to help compute a better ephemeris for this distant object. Astronomer James W. Christy had noticed that a number of the images of Pluto appeared elongated, but images of background stars on the same plate did not. Other plates showed the planet as a tiny, round dot. Christy examined a number of Pluto images from the USNO archives, and he noticed the elongations again. Furthermore, the elongations appeared to change position with respect to the stars over time. After eliminating the possibility that the elongations were produced by plate defects and background stars, the only plausible explanation was that they were caused by a previously unknown moon orbiting Pluto at a distance of about 19,600 kilometers (12,100 miles) with a period of just over six days. On 7 July 1978, the discovery was formally announced to the astronomical community and the world by the IAU Central Bureau for Astronomical Telegrams via IAU Circular 3241. The discovery received the provisional designation "1978 P 1"; Christy proposed the name "Charon", after the mythological ferryman who carried souls across the river Acheron, one of the five mythical rivers that surrounded Pluto's underworld. Over the course of the next several years, another USNO astronomer, the late Robert S. Harrington, calculated that Pluto and its newly-found moon would undergo a series of mutual eclipses and occultations, beginning in early 1985. On 17 February 1985 the first successful observation of one of these transits was made at with the 0.9-meter (36-inch) reflector at the University of Texas McDonald Observatory, within 40 minutes of Harrington's predicted time. The IAU Circular announcing these confirming observations was issued on 22 February 1985. With this confirmation, the new moon was officially named Charon. Pluto was discovered at Lowell Observatory in 1930 by the late Clyde W. Tombaugh, an amateur astronomer from Kansas who was hired by the Observatory specifically to photograph the sky with a special camera and search for the planet predicted by the Observatory's founder, Percival Lowell. Lowell had deduced the existence of a "Planet X" by studying small anomalies in the orbits of Uranus and Neptune. As it turned out, Pluto's discovery was almost entirely serendipitous; Pluto's tiny mass was far too small to account for the anomalies, which were resolved when Voyager 2 determined more precise masses for Uranus and Neptune. The discovery of Charon has led to a much better understanding of just how tiny Pluto is. Its diameter is about 2274 km (1413 miles), and its mass is 0.25% of the mass of the Earth. Charon has a diameter of about 1172 kilometers (728 miles) and a mass of about 22% that of Pluto. The two worlds circle their common center of mass with a period of 6.387 days and are locked in a "super-synchronous" rotation: observers on Pluto's surface would always see Charon in the same part of the sky relative to their local horizon. Normally Pluto is considered the most distant world in the solar system, but during the period from January 1979 until February 1999 it was actually closer to the Sun than Neptune. It has the most eccentric and inclinced orbit of any of the major planets. This orbit won't bring Pluto back to its discovery position until the year 2178! # Plasma objects The New Horizons Particles and Plasma team has discovered a region of cold, dense ionized gas tens of thousands of miles beyond Pluto -- the planet's atmosphere being stripped away by the solar wind and lost to space. # 2015 TG387 2015 TG387 (nicknamed The Goblin for the letters TG and because its discovery was near Halloween), is a trans-Neptunian object (TNO) and sednoid in the outermost part of the Solar System. It was first observed on October 13, 2015, with the Subaru Telescope at Mauna Kea Observatories, and publicly announced on October 1, 2018. 2015 TG387 is the third sednoid to be discovered, following 90377 Sedna and 2012 VP113. It is estimated to be 300 km (186.4113576 mi) in diameter. Along with the similar orbits of other distant TNOs, the orbit of 2015 TG387 suggests, but does not prove, the existence of a hypothetical Planet Nine in the outer Solar System. As of 2018, the object is 80 AU from the Sun; about two-and-a-half times farther out than Pluto’s orbit. As with Sedna, it would not have been found had it not been on the inner leg of its long orbit, which suggests that there may be many similar objects, most too distant to be detected by contemporary technological methods, and implies a population of about 2 million Hills cloud, or inner Oort cloud, objects larger than 40 km (24.85484768 mi), with a combined total mass of 1022 kg, which is several times the mass of the asteroid belt. # Cubewanos The classical objects (cubewanos) are very different from the scattered objects: more than 30% of all cubewanos are on low-inclination, near-circular orbits whose eccentricities peak at 0.25. Classical objects possess eccentricities ranging from 0.2 to 0.8. Though the inclinations of scattered objects are similar to the more extreme KBOs, very few scattered objects have orbits as close to the ecliptic as much of the KBO population. Although motions in the scattered disc are random, they do tend to follow similar directions, which means that SDOs can become trapped in temporary resonances with Neptune. Examples of possible resonant orbits within the scattered disc include 1:3, 2:7, 3:11, 5:22 and 4:79. # Plutinos The Kuiper belt is a relatively thick torus (or "doughnut") of space, extending from about 30 to 50 AU comprising two main populations of Kuiper belt objects (KBOs): the classical Kuiper-belt objects (or "cubewanos"), which lie in orbits untouched by Neptune, and the resonant Kuiper-belt objects; those which Neptune has locked into a precise orbital ratio such as 2:3 (the object goes around twice for every three Neptune orbits) and 1:2 (the object goes around once for every two Neptune orbits). These ratios, called orbital resonances, allow KBOs to persist in regions which Neptune's gravitational influence would otherwise have cleared out over the age of the Solar System, since the objects are never close enough to Neptune to be scattered by its gravity. Those in 2:3 resonances are known as "plutinos", because Pluto is the largest member of their group, whereas those in 1:2 resonances are known as "resonant trans-Neptunian object#1:2 resonance ("twotinos", period ~330 years) twotinos". # Kuiper belts The Kuiper belt is a region of the solar system extending from the orbit of Neptune (at 30 AU to approximately 60 AU from the Sun. It consists mainly of small bodies. "roadband optical photometry of Centaurs and Kuiper Belt objects from the Keck 10 m, the University of Hawaii 2.2 m, and the Cerro Tololo InterAmerican (CTIO) 1.5 m telescopes a wide dispersion in the optical colors of the objects, indicating nonuniform surface properties. The color dispersion be understood in the context of the expected steady reddening due to bombardment by the ubiquitous flux of cosmic rays." In the image at right, objects in the main part of the Kuiper belt are coloured green, while scattered objects are coloured orange. The four outer planets are blue. Neptune's few known trojans are yellow, while Jupiter's are pink. The scattered objects between Jupiter's orbit and the Kuiper belt are known as centaurs. The scale is in astronomical units. The pronounced gap at the bottom is due to difficulties in detection against the background of the plane of the Milky Way. Legend: - Red = The Sun - Aquamarine = Giant Planet - Lime Green = Kuiper belt object - Orange = Scattered disc object or Centaur - Magenta = Trojan of Jupiter - Yellow = Trojan of Neptune Axes list distances in AU, projected onto the ecliptic, with ecliptic longitude zero being to the right, along the "x" axis). Positions are accurate for January 1st, 2000 (J2000 epoch) with some caveats: For planets, positions should be exact. For minor bodies, positions are extrapolated from other epochs assuming purely Keplerian motion. As all data is from an epoch between 1993 and 2007, this should be a reasonable approximation. Data from the Minor Planet Center or Murray and Dermott as needed. Radial "spokes" of higher density in this image, or gaps in particular directions are due to observational bias (i.e. where objects were searched for), rather than any real physical structure. The pronounced gap at the bottom is due to obscuration by the band of the Milky Way. # 1995 TL 95 The first object presently classified as an SDO to be discovered was 1995 TL8, found in 1995 by Spacewatch. # 1996 TL 96 The first scattered-disc object (SDO) to be recognised as such was 1996 TL66, originally identified in 1996 by astronomers based at Mauna Kea in Hawaii. # 1999 CV 118 Three more were identified by the same survey in 1999: 1999 CV118, 1999 CY118, and 1999 CF119. # 2011 SDOs As of 2011, over 200 SDOs have been identified, including 229762 Gǃkúnǁʼhòmdímà|Gǃkúnǁʼhòmdímà (discovered by Schwamb, Brown, and Rabinowitz), 2002 TC302 (Near Earth Asteroid Tracking NEAT), Eris (Brown, Trujillo, and Rabinowitz), 90377 Sedna Sedna (Brown, Trujillo, and Rabinowitz) and 2004 VN112 (Deep Ecliptic Survey). Although the numbers of objects in the Kuiper belt and the scattered disc are hypothesized to be roughly equal, observational bias due to their greater distance means that far fewer SDOs have been observed to date. # Oort clouds The Oort cloud or the Öpik–Oort cloud is a hypothesized spherical cloud of comets which may lie roughly 50,000 AU, or nearly a light-year, from the Sun. This places the cloud at nearly a quarter of the distance to Proxima Centauri, the nearest star to the Sun. The outer limit of the Oort cloud defines the cosmographical boundary of the Solar System and the region of the Sun's gravitational dominance. Known trans-Neptunian objects are often divided into two subpopulations: the Kuiper belt and the scattered disc. A third reservoir of trans-Neptunian objects, the Oort cloud, has been hypothesized, although no confirmed direct observations of the Oort cloud have been made. Some researchers further suggest a transitional space between the scattered disc and the inner Oort cloud, populated with "detached objects". # Neptune objects In contrast to the Kuiper belt, the scattered-disc population can be disturbed by Neptune. Scattered-disc objects come within gravitational range of Neptune at their closest approaches (~30 AU) but their farthest distances reach many times that. Ongoing research suggests that the centaurs, a class of icy planetoids that orbit between Jupiter and Neptune, may simply be SDOs thrown into the inner reaches of the Solar System by Neptune, making them "cis-Neptunian" rather than trans-Neptunian scattered objects. Some objects, like (29981) 1999 TD10, blur the distinction and the Minor Planet Center (MPC), which officially catalogues all trans-Neptunian objects, now lists centaurs and SDOs together. The MPC, however, makes a clear distinction between the Kuiper belt and the scattered disc, separating those objects in stable orbits (the Kuiper belt) from those in scattered orbits (the scattered disc and the centaurs). However, the difference between the Kuiper belt and the scattered disc is not clear-cut, and many astronomers see the scattered disc not as a separate population but as an outward region of the Kuiper belt. Another term used is "scattered Kuiper-belt object" (or SKBO) for bodies of the scattered disc. The difference between objects in the Kuiper belt and scattered-disc objects is that the latter bodies "are transported in semi-major axis by close and distant encounters with Neptune," but the former experienced no such close encounters. This delineation is inadequate (as they note) over the age of the Solar System, since bodies "trapped in resonances" could "pass from a scattering phase to a non-scattering phase (and vice versa) numerous times." That is, trans-Neptunian objects could travel back and forth between the Kuiper belt and the scattered disc over time. Therefore, they chose instead to define the regions, rather than the objects, defining the scattered disc as "the region of orbital space that can be visited by bodies that have encountered Neptune" within the radius of a Hill sphere, and the Kuiper belt as its "complement ... in the a > 30 AU region"; the region of the Solar System populated by objects with semi-major axes greater than 30 AU. The scattered disc is a very dynamic environment. Because they are still capable of being perturbed by Neptune, SDOs' orbits are always in danger of disruption; either of being sent outward to the Oort cloud or inward into the centaur population and ultimately the Jupiter family of comets. For this reason Gladman et al. prefer to refer to the region as the scattering disc, rather than scattered. Unlike Kuiper-belt objects (KBOs), the orbits of scattered-disc objects can be inclined as much as 40° from the ecliptic. # Sedna Sedna was discovered from an image dated 2003-11-14 at coordinates 03 15 10.09 +05 38 16.5. The 3 overexposed stars are apparent magnitude 13. The "bright star" near Sedna is apmag 14.9 and about the same magnitude as Pluto. (Wikisky image of this region) The picture shows an area of the sky equal to the area covered by a pinhead held at arm's length. Sedna is too faint to be seen by all but the most powerful amateur telescopes. The Minor Planet Center classifies the trans-Neptunian object 90377 Sedna as a scattered-disc object. Sedna should be considered an inner Oort-cloud object rather than a member of the scattered disc, because, with a perihelion distance of 76 AU, it is too remote to be affected by the gravitational attraction of the outer planets. Under this definition, an object with a perihelion greater than 40 AU could be classified as outside the scattered disc. # 2000 CR 105 (148209) 2000 CR105 (discovered before Sedna) and 2004 VN112 have a perihelion too far away from Neptune to be influenced by it. This led to a discussion among astronomers about a new minor planet set, called the extended scattered disc (E-SDO). 2000 CR105 may also be an inner Oort-cloud object or (more likely) a transitional object between the scattered disc and the inner Oort cloud. More recently, these objects have been referred to as "detached", or distant detached objects (DDO). There are no clear boundaries between the scattered and detached regions. Gomes et al. define SDOs as having "highly eccentric orbits, perihelia beyond Neptune, and semi-major axes beyond the 1:2 resonance." By this definition, all distant detached objects are SDOs. Since detached objects' orbits cannot be produced by Neptune scattering, alternative scattering mechanisms have been put forward, including a passing star or a distant, planet-sized object. # Scattered near objects Scattered-near (i.e. typical SDOs) and scattered-extended (i.e. detached objects), where scattered-near objects are those whose orbits are non-resonant, non-planetary-orbit-crossing and have a Tisserand parameter (relative to Neptune) less than 3, and scattered-extended objects have a Tisserand parameter (relative to Neptune) greater than 3 and have a time-averaged eccentricity greater than 0.2. # 10-million-year orbits A 10-million-year orbit integration is used instead of the Tisserand parameter. An object qualifies as an SDO if its orbit is not resonant, has a semi-major axis no greater than 2000 AU, and, during the integration, its semi-major axis shows an excursion of 1.5 AU or more. Gladman et al. suggest the term scattering disk object to emphasize this present mobility. If the object is not an SDO as per the above definition, but the eccentricity of its orbit is greater than 0.240, it is classified as a detached TNO. (Objects with smaller eccentricity are considered classical.) In this scheme, the disc extends from the orbit of Neptune to 2000 AU, the region referred to as the inner Oort cloud. # Medium and high eccentricities SDOs are typically characterized by orbits with medium and high eccentricities with a semi-major axis greater than 50 AU, but their perihelia bring them within influence of Neptune. Having a perihelion of roughly 30 AU is one of the defining characteristics of scattered objects, as it allows Neptune to exert its gravitational influence. # Eris 136199 Eris was measured to be 2,326  (Expression error: Unexpected round operator. ) in diameter. Eris's mass is about 0.27% of the Earth mass, about 27% more than dwarf planet Pluto, although Pluto is slightly larger by volume. Eris is a trans-Neptunian object (TNO), a member of a high-orbital eccentricity population known as the scattered disk, with one known natural satellite, Dysnomia, at a distance from the Sun of 96.3 astronomical units (Expression error: Missing operand for *. ), roughly three times that of Pluto. With the exception of some long-period comets, until 2018 VG18 was discovered on December 17, 2018, Eris and Dysnomia were the most distant known natural objects in the Solar System. Observations of a stellar occultation by Eris in 2010 showed that its diameter was 2,326  (Expression error: Unexpected round operator. ), very slightly less than Pluto, which was measured by New Horizons as 2,376.6  (Expression error: Unexpected round operator. ) in July 2015. Eris is a trans-Neptunian dwarf planet (plutoid). Its orbital characteristics more specifically categorize it as a scattered-disk object (SDO), or a TNO that has been "scattered" from the Kuiper belt into more-distant and unusual orbits following gravitational interactions with Neptune as the Solar System was forming. Although its high orbital inclination is unusual among the known SDOs, theoretical models suggest that objects that were originally near the inner edge of the Kuiper belt were scattered into orbits with higher inclinations than objects from the outer belt. # Haumea Haumea (minor-planet designation 136108 Haumea, initially, (136108) 2003 EL61) is a dwarf planet located beyond Neptune's orbit. It was discovered on December 28, 2004, just after Christmas, at the Palomar Observatory. Precovery images of Haumea have been identified back to March 22, 1955. Haumea is a plutoid, a dwarf planet located beyond Neptune's orbit. The nominal trajectory suggests that Haumea is in a weak 7:12 orbital resonance with Neptune, which would make it a resonant trans-Neptunian object instead. There are precovery images of Haumea dating back to March 22, 1955 from the Palomar Mountain Digitized Sky Survey. Haumea has an orbital period of 284 Earth years, a perihelion of 35 AU, and an orbital inclination of 28°. It passed aphelion in early 1992, and is currently more than 50 AU from the Sun. Haumea's orbit has a slightly greater orbital eccentricity than that of the other members of the Haumea family, its collisional family. This is thought to be due to Haumea's weak 7:12 orbital resonance with Neptune gradually modifying its initial orbit over the course of a billion years, through the Kozai mechanism, or Kozai effect, which allows the exchange of an orbit's inclination for increased eccentricity. With a visual magnitude of 17.3, Haumea is the third-brightest object in the Kuiper belt after Pluto and Makemake, and easily observable with a large amateur telescope. However, because the planets and most small Solar System bodies share a invariable plane, or common orbital alignment, from their formation in the protoplanetary, primordial disk, of the Solar System, most early surveys for distant objects focused on the projection on the sky of this common plane, called the ecliptic. As the region of sky close to the ecliptic became well explored, later sky surveys began looking for objects that had been dynamically excited into orbits with higher inclinations, as well as more distant objects, with slower mean motions across the sky. Haumea displays large fluctuations in brightness over a period of 3.9 hours, which can only be explained by a rotational period of this length. This is faster than any other known equilibrium body in the Solar System, and indeed faster than any other known body larger than 100 km in diameter. While most rotating bodies in equilibrium are flattened into oblate spheroids, Haumea rotates so quickly that it is distorted into a triaxial ellipsoid. If Haumea were to rotate much more rapidly, it would distort itself into a dumbbell shape and split in two. This rapid rotation is thought to have been caused by the impact that created its satellites and collisional family. Because Haumea has moons, the mass of the system can be calculated from their orbits using Kepler's third law. The result is 4.2Template:E kg, 28% the mass of the Plutonian system and 6% that of the Moon. Nearly all of this mass is in Haumea. For most distant objects, the albedo is unknown, but Haumea is large and bright enough for its infrared, thermal emission to be measured, which has given an approximate value for its albedo and thus its size. The rigid body dynamics, specifically, rotational physics of deformable bodies predicts that over as little as a hundred days, a body rotating as rapidly as Haumea will have been distorted into the hydrostatic equilibrium form of a triaxial ellipsoid. It is thought that most of the fluctuation in Haumea's brightness is caused not by local differences in albedo but by the alternation of the side view and end view as seen from Earth. If Haumea were in hydrostatic equilibrium and had a low density like Pluto, with a thick mantle of volatiles, such as ice, over a small silicate, rocky core, its rapid rotation would have elongated it to a greater extent than the fluctuations in its brightness allow. Such considerations constrained its density to a range of 2.6–3.3 g/cm3. In 2005, the Gemini Observatory and Keck Observatory telescopes obtained spectra of Haumea which showed strong crystalline water ice features similar to the surface of Pluto's moon Charon. This is peculiar, because crystalline ice forms at temperatures above 110 K, whereas Haumea's surface temperature is below 50 K, a temperature at which amorphous ice is formed. In addition, the structure of crystalline ice is unstable under the constant rain of cosmic rays and energetic particles from the Sun that strike trans-Neptunian objects. The timescale for the crystalline ice to revert to amorphous ice under this bombardment is on the order of ten million years, yet trans-Neptunian objects have been in their present cold-temperature locations for timescales of billions of years. Radiation damage should also redden and darken the surface of trans-Neptunian objects where the common surface materials of organic molecular ices and tholin-like compounds are present, as is the case with Pluto. Therefore, the spectra and colour suggest Haumea and its family members have undergone recent resurfacing that produced fresh ice. However, no plausible resurfacing mechanism has been suggested. Haumea is as bright as snow, with an albedo in the range of 0.6–0.8, consistent with crystalline ice. Other large TNOs such as Eris appear to have albedos as high or higher. Best-fit modeling of the surface spectra suggested that 66% to 80% of the Haumean surface appears to be pure crystalline water ice, with one contributor to the high albedo possibly hydrogen cyanide or phyllosilicate clays. Inorganic cyanide salts such as copper potassium cyanide may also be present. Visible and near infrared spectra suggest a homogeneous surface covered by an intimate 1:1 mixture of amorphous and crystalline ice, together with no more than 8% organics. The absence of ammonia hydrate excludes cryovolcanism and the observations confirm that the collisional event must have happened more than 100 million years ago, in agreement with the dynamic studies. The absence of measurable methane in the spectra of Haumea is consistent with a warm collisional history that would have removed such volatiles, in contrast to Makemake. # Interstellar comets An interstellar object is an astronomical object that is located in interstellar space including objects that are on an interstellar trajectory but are temporarily passing close to a star, such as certain asteroids and comets (including exocomets) The image on the right shows `Oumuamua's hyperbolic trajectory across the full solar system, with annual markers, and planet positions on 1/1/2018. "A newly discovered comet is screaming away from Earth, and based on its weird orbital trajectory might be the first comet ever observed to come from interstellar space. A sky-surveying telescope in Hawaii spotted the fast-moving object, now called C/2017 U1, on 18 October, after its closest approach to the sun. The following week, astronomers made 34 separate observations of the object and found it has a strange trajectory that doesn't appear to circle the sun." ʻOumuamua showed no signs of a cometary coma despite its close approach to the Sun, but underwent non-gravitational acceleration which is seen in many icy comets, although other reasons have been suggested. The object could be a remnant of a disintegrated interstellar comet (or exocomet). It is possible for objects orbiting a star to be ejected due to interaction with a third massive body, such a process was initiated in early 1980s when C/1980 E1, initially gravitationally bound to the Sun, passed near Jupiter and was accelerated sufficiently to reach escape velocity from the Solar System, changing its orbit from elliptical to hyperbolic and making it the most eccentric known object at the time, with an eccentricity of 1.057. It is headed for interstellar space. Asteroid (514107) 2015 BZ509 may be a former interstellar object, captured some 4.5 billion years ago, as evidenced by its co-orbital motion with Jupiter and its retrograde orbit around the Sun. An interstellar comet can probably, on rare occasions, be captured into a heliocentric orbit while passing through the Solar System. Computer simulations show that Jupiter is the only planet massive enough to capture one, and that this can be expected to occur once every sixty million years. Comets Machholz 1 and Comet Hyakutake C/1996 B2 are possible examples of such comets, as they have atypical chemical makeups for comets in the Solar System. Current models of Oort cloud formation predict that more comets are ejected into interstellar space than are retained in the Oort cloud, with estimates varying from 3 to 100 times as many. Other simulations suggest that 90–99% of comets are ejected. There is no reason to believe comets formed in other star systems would not be similarly scattered. A more recent estimate, following the detection of 'Oumuamua, predicts that "The steady-state population of similar, ~100 m scale interstellar objects inside the orbit of Neptune is ~1Template:E, each with a residence time of ~10 years." There should be hundreds of 'Oumuamua-size interstellar objects in the Solar System, based on calculated orbital characteristics, with known examples: 2011 SP25, 2017 RR2, 2017 SV13, and 2018 TL6. These are all orbiting the sun, but with unusual orbits, and are assumed to have been trapped at some occasion. # Acknowledgements The content on this page was first contributed by: Henry A. Hoff. Initial content for this page in some instances came from Wikiversity.

Red eye resident survival guide (pediatrics) Synonyms and keywords: Approach to red eye in children, Red-eye work-up in kids, Red-eye management in children # Overview Red eye is one of the most common ophthalmologic conditions in the primary care setting in children. Inflammation of almost any part of the eye, including the lacrimal glands and eyelids, or faulty tear film can lead to red eye. Primary care physicians often effectively manage red eye, although knowing when to refer patients to an ophthalmologist is crucial, baseline ophthalmological tests, and accompanying manifestations can narrow down the differential diagnosis. The duration and laterality of symptoms (unilateral- vs. bilateral) and the intensity of pain are the main criteria allowing the differentiation of non-critical changes that can be cared for a general practitioner from diseases calling for an elective referral to an ophthalmologist and eye emergencies requiring urgent ophthalmic surgery. # Causes ## Life Threatening Causes Life-threatening causes include conditions that could lead to death or permanent disability within 24 hours if left untreated. - Globe ruptures or perforations - Intraocular infections - Carotid–cavernous sinus fistula ## Common Causes ### Infectious - Bacterial conjunctivitis - Viral conjunctivitis - Iritis/iridocyclitis - Anterior uveitis - Posterior uveitis (choroiditis) - Endophthalmitis - Dacrocystitis ### Non-infectious - Acute angle-closure glaucoma - Disorders of the ocular adnexa(Hordeolum-Eyelid malposition) - Eyelid malposition - Intraocular disorders - Scleritis/Episcleritis - Photokeratitis - Corneal erosion/ulceration - Subconjunctival hemorrhage - Allergic conjunctivitis - Non-infectious (kerato)conjunctivitis - Contact lens - Blunt or penetrating trauma - foreign bodies - Chemical conjunctivitis - Blepharitis # FIRE: Focused Initial Rapid Evaluation Patients with the primary symptom of a red eye are commonly seen in pediatric primary care clinics. The differential diagnoses of a red eye are broad, but with a succinct history and physical examination, the diagnosis can be readily identified in many patients. Identifying conditions that threaten vision and understanding the urgency of referral to an ophthalmologist is paramount. Some systemic diseases such as leukemia, sarcoidosis, and juvenile idiopathic arthritis can present with the chief symptom of a red eye. Finally, trauma, ranging from mild to severe, often precipitates an office visit with a red eye, and thus understanding the signs that raise concern for a ruptured globe is essential . In the primary care setting, with a focused history, a few simple examination techniques, and an appreciation of the differential diagnosis, one can feel confident in managing patients with acute red eyes., or eye emergencies requiring urgent ophthalmic surgery. # Complete Diagnostic Approach Red eye in pediatrics cab be divided into Localized, diffused and peri keratic injection. Shown below is an algorithm summarizing the diagnosis of red eye according to the Nelson Essentials of Pediatrics guidelines. # Treatment Shown below is an algorithm summarizing the treatment of Red eye according to the American journal of medicine. - Good hygiene, such as meticulous hand washing, is important in decreasing the spread of acute viral conjunctivitis. - Any ophthalmic antibiotic may be considered for the treatment of acute bacterial conjunctivitis because they have similar cure rates. - Mild allergic conjunctivitis may be treated with an over-the-counter antihistamine/vasoconstrictor agent, or with a more effective second-generation topical histamine H1 receptor antagonist. - Anti-inflammatory agents (e.g., topical cyclosporine), topical corticosteroids, and systemic omega-3 fatty acids are appropriate therapies for moderate dry eye. - Patients with chronic blepharitis who do not respond adequately to eyelid hygiene and topical antibiotics may benefit from an oral tetracycline or doxycycline. # Do's - The most important task is to detect potentially serious ocular presentations to the immediate referral of the patient to an ophthalmologist and treatment. - Conditions requiring referral to an ophthalmologist are orbital cellulitis, hyphaema, scleritis, iritis or uveitis, acute angle closure glaucoma, and corneal abrasions (unless very superficial). - Be cautious when prescribing steroids: You should exclude the possibility of herpetic keratitis. - Ocular pain and change in vision are two extremely specific warning signs of eye pathology, and unless doctor are absolutely certain of a benign diagnosis doctor must refer him for ophthalmological assessment if he has these. # Don'ts - Do not miss the pupillary exam in the pediatric population is a vital part of any clinician's workup. In the right clinical setting, pupillary abnormalities such as anisocoria, light-near dissociation, an afferent pupillary defect, and paradoxic pupillary constriction in the dark can be red flags that trigger further examination and workup. - Through both careful physical examination and detailed history taking and observation, potentially vision- and life-threatening conditions can be detected.

Structural genomics Structural genomics consists in the determination of the three dimensional structure of all proteins of a given organism, by experimental methods such as X-ray crystallography, NMR spectroscopy or computational approaches such as homology modelling. As opposed to traditional structural biology, the determination of a protein structure through a structural genomics effort often (but not always) comes before anything is known regarding the protein function. This raises new challenges in structural bioinformatics, i.e. determining protein function from its 3D structure. Structural genomics emphasizes high throughput determination of protein structures. This is performed in dedicated centers of structural genomics. While most structural biologists pursue structures of individual proteins or protein groups, specialists in structural genomics pursue structures of proteins on a genome wide scale. This implies large scale cloning, expression and purification. One main advantage of this approach is economy of scale. On the other hand, the scientific value of some resultant structures is at times questioned. A Science article from January 2006 analyzes the structural genomics field. One advantage of structural genomics, such as the Protein Structure Initiative, is that the scientific community gets immediate access to new structures, as well as to reagents such as clones and protein. A disadvantage is that many of these structures are of proteins of unknown function and do not have corresponding publications. This lack of publications is not entirely unanticipated in that a change in the way how protein structures are determined would require corresponding changes in the way this structural information is communicated to the broader research community. The Bioinformatics core of the Joint center for structural genomics (JCSG) has recently developed a wiki-based approach namely The Open Protein Structure Annotation Network (TOPSAN) for annotating protein structures emerging from high-throughput structural genomics centers. Some of the pros and cons of the Protein Structure Initiative are discussed in the December 2007 and January 2008 issues of the journal Structure. It is sometimes assumed that the technical quality of structural genomics structures is lower than that of traditional structures, but this has been shown to be false.

Dill Dill (Anethum graveolens) is a short-lived annual herb, native to southwest and central Asia. It is the sole species of the genus Anethum, though classified by some botanists in the related genus Peucedanum as Peucedanum graveolens (L.) C.B.Clarke. It grows to 40-60 cm tall, with slender stems and alternate, finely divided, softly delicate leaves 10-20 cm long. The ultimate leaf divisions are 1-2 mm broad, slightly broader than the similar leaves of fennel, which are threadlike, less than 1 mm broad, but harder in texture. The flowers are white to yellow, in small umbels 2-9 cm diameter. The seeds are 4-5 mm long and 1 mm thick, and straight to slightly curved with a longitudinally ridged surface. Its seeds, dill seed are used as a spice, and its fresh leaves, dill, and its dried leaves, dill weed, are used as herbs. # Origins and history Dill originated in central Asia. Zohary and Hopf remark that "wild and weedy types of dill are widespread in the Mediterranean basin and in West Asia." Although several twigs of dill were found in the tomb of Amenhotep II, they report that the earliest archeological evidence for its cultivation comes from late Neolithic lake shore settlements in Switzerland. Traces have been found in Roman ruins in Great Britain. In Semitic languages it is known by the name of Shubit. The Talmud requires that tithes shall be paid on the seeds, leaves, and stem of dill. The Bible states that the Pharisees were in the habit of paying dill as tithe (Matthew 23:23) ; Jesus Christ is said to have rebuked them for tithing dill but omitting mercy. # Name The name dill is thought to have originated from a Norse or Anglo-Saxon word 'dylle' meaning to soothe or lull, the plant having the carminative property of relieving gas. In some English speaking countries, it is sometimes called Dillby. In some Asian local languages it is called as "Shepu" or "Sowa". # Uses Fresh and dried dill leaves (sometimes called "dill weed" to distinguish it from dill seed) are used as herbs. Like caraway, its fernlike leaves are aromatic, and are used to flavor many foods, such as gravlax (cured salmon), borscht and other soups, and pickles. Dill is said to be best when used fresh, as it lose its flavor rapidly if dried; however, freeze-dried dill leaves preserve their flavor relatively well for a few months. In the Middle Ages, dill was thought to protect against witchcraft. Dill seed is used as a spice, with a flavor similar to caraway. Dill oil can be extracted from the leaves, stems and seeds of the plant. Medicinal value - Dill is an herb effective for the treatment of colic, gas, and indigestion. # Cultivation Successful cultivation requires warm to hot summers with high sunshine levels; even partial shade will reduce the yield substantially. It also prefers rich, well drained soil. The seeds are viable for 3-10 years. Plants intended for seed for further planting should not be grown near fennel, as the two species can hybridise. The seed is harvested by cutting the flower heads off the stalks when the seed is beginning to ripen. The seed heads are placed upside down in a paper bag and left in a warm dry place for a week. The seeds then separate from the stems easily for storage in an airtight container.

Nevus of Ota # Overview Nevus of Ota (also known as "congenital melanosis bulbi", "nevus fuscoceruleus ophthalmomaxillaris", "oculodermal melanocytosis",:700 and "Oculomucodermal melanocytosis") is a blue hyperpigmentation that occurs on the face. It was first reported by Dr. M. T. Ota of Japan in 1939. Nevus of Ota is caused by the entrapment of melanocytes in the upper third of the dermis. It is found on the face unilaterally and involves the first two branches of the trigeminal nerve. The sclera is involved in two-thirds of cases (causing an increased risk of glaucoma). It should not be confused with Mongolian spot, which is a birthmark caused by entrapment of melanocytes in the dermis but is located in the lumbosacral region. Women are nearly five times more likely to be affected than men, and it is rare among caucasian people. Nevus of Ota may not be congenital, and may appear during puberty. # Diagnosis ## Physcial Examination ### Eye - Naevus of ota. With permission from Dermatology Atlas. - Naevus of ota- bilateral type. With permission from Dermatology Atlas. # Treatment A Q-switched laser has been successfully used to treat the condition. Hydroquinone preparations are also helpful in partially treating this condition.

Acetaminophen (patient information) # IMPORTANT WARNING The Centers for Disease Control and Prevention (CDC) issued a Morbidity and Mortality Weekly Report (MMWR) article describing three deaths in U.S. infants aged less than 12 months associated with cough and cold medications. These medications were determined by medical examiners or coroners to be the underlying cause of death. The cases described in this report underscore the need for clinicians to use caution when prescribing and caregivers to use caution when administering cough and cold medications to children aged less than 2 years. For more information visit the FDA website at: #coughcold and . # Why this medication is prescribed Acetaminophen is used to relieve mild to moderate pain from headaches, muscle aches, menstrual periods, colds and sore throats, toothaches, backaches, reactions to vaccinations (shots), and to reduce fever. Acetaminophen may also be used to relieve the pain of osteoarthritis (arthritis caused by the breakdown of the lining of the joints). Acetaminophen is in a class of medications called analgesics and antipyretics. It works by changing the way the body senses pain and by cooling the body. # How this medication should be used Acetaminophen comes as a tablet, chewable tablet, capsule, suspension or solution (liquid), drops (concentrated liquid), extended-release (long-acting) tablet, and orally disintegrating tablet (tablet that dissolves quickly in the mouth), to take by mouth, with or without food. Acetaminophen also comes as a suppository to use rectally. Acetaminophen is available without a prescription, but your doctor may prescribe acetaminophen to treat certain conditions. Follow the directions on the package or prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take acetaminophen exactly as directed. Do not take more or less of it or take it more often than directed on the package label or prescribed by your doctor. Taking more than the recommended amount may cause damage to your liver. If you are giving acetaminophen to your child, check the chart on the package to find out how much medication the child needs. If you know how much your child weighs, give the dose that matches that weight on the chart. If you don't know your child's weight, give the dose that matches your child's age. Do not give children acetaminophen products that are made for adults. Ask your child's doctor if you don't know how much medication to give your child. Swallow the extended-release tablets whole; do not split, chew, crush, or dissolve them. Place the orally disintegrating tablet in your mouth and allow to dissolve or chew it before swallowing. Shake the suspension and drops well before each use to mix the medication evenly. Use the measuring cup provided by the manufacturer to measure each dose of the solution or suspension, and use the dosing device provided to measure each dose of the drops. Use the dosing device to slowly release the drops directly into the child's mouth near the inner cheek. Do not mix the drops with baby formula. To insert an acetaminophen suppository into the rectum, follow these steps: - Remove the wrapper. - Dip the tip of the suppository in water. - Lie down on your left side and raise your right knee to your chest. (A left-handed person should lie on the right side and raise the left knee.) - Using your finger, insert the suppository into the rectum, about ½ to 1 inch in infants and children and 1 inch in adults. Hold it in place for a few moments. - Stand up after about 15 minutes. Wash your hands thoroughly and resume your normal activities. Stop taking acetaminophen and call your doctor if your symptoms get worse, you develop new or unexpected symptoms, the part of your body that was painful becomes red or swollen, your pain lasts for more than 10 days, or your fever gets worse or lasts more than 3 days. Also stop giving acetaminophen to your child and call your child's doctor if your child develops new symptoms, including redness or swelling on the painful part of his body, or your child's pain lasts for longer than 5 days or fever get worse or lasts longer than 3 days. Do not give acetaminophen to a child who has a sore throat that is severe or does not go away, or that comes along with fever, headache, rash, nausea, or vomiting. Call the child's doctor right away, because these symptoms may be signs of a more serious condition. # Other uses for this medicine Acetaminophen may also be used in combination with aspirin and caffeine to relieve the pain associated with migraine headache. This medication is sometimes prescribed for other uses; ask your doctor or pharmacist for more information. # Special precautions Before taking acetaminophen: - tell your doctor and pharmacist if you are allergic to acetaminophen, any other medications, or any of the ingredients in the product. - do not take more two or more products that contain acetaminophen at the same time. Many prescription and nonprescription medications contain acetaminophen in combination with other medications. Read the package labels or ask your doctor or pharmacist to be sure that you do not take more than one product that contains acetaminophen at a time. - tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, or herbal products you are taking or plan to take. Be sure to mention anticoagulants ('blood thinners') such as warfarin (Coumadin); isoniazid (INH); certain medications for seizures including carbamazepine (Tegretol), phenobarbital, and phenytoin (Dilantin); medications for pain, fever, coughs, and colds; and phenothiazines (medications for mental illness and nausea); Your doctor may need to change the doses of your medications or monitor you carefully for side effects. - tell your doctor if you have any serious medical condition. - tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking acetaminophen, call your doctor. - if you drink three or more alcoholic beverages every day, ask your doctor if you should take acetaminophen. Ask your doctor or pharmacist about the safe use of alcoholic beverages while taking acetaminophen. - if you have phenylketonuria (PKU, a inherited condition in which a special diet must be followed to prevent mental retardation), you should know that some brands of the chewable tablets may contain phenylalanine. # Special dietary instructions Unless your doctor tells you otherwise, continue your normal diet. # What to do if you forget a dose This medication is usually taken as needed. If your doctor has told you to take acetaminophen regularly, take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one. # Side Effects Acetaminophen may cause side effects. Some side effects can be serious. If you experience any of the following symptoms, call your doctor immediately: - rash - hives - itching - swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs - hoarseness - difficulty breathing or swallowing Acetaminophen may cause other side effects. Call your doctor if you have any unusual problems while you are taking this medication. If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online or by phone . # Storage conditions needed for this medication Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication. # In case of emergency/overdose Return to top In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911. If someone takes more than the recommended dose of acetaminophen, get medical help immediately, even if the person does not have any symptoms. Symptoms of overdose may include: - nausea - vomiting - loss of appetite - sweating - extreme tiredness - unusual bleeding or bruising - pain in the upper right part of the stomach - yellowing of the skin or eyes - flu-like symptoms # Other information Before having any laboratory test, tell your doctor and the laboratory personnel that you are taking acetaminophen. Ask your pharmacist any questions you have about acetaminophen. # Brand names - Acephen® - Anacin® Aspirin Free Maximum Strength Tablets® - Capital® and Codeine - Endocet® - Excedrin P.M.® Caplets® - Excedrin P.M.® Geltabs® - Excedrin P.M.® Tablets - Excedrin® Extra-Strength Caplets® - Excedrin® Extra-Strength Tablets - Excedrin® Migraine Caplets® - Excedrin® Migraine Geltabs - Excedrin® Migraine Tablets - FeverAll® Children's - FeverAll® Infants' - FeverAll® Junior Strength - Gelpirin® - Genapap® - Genapap® Children's - Genapap® Drops Infant's - Genapap® Extra Strength Caplets® - Genapap® Extra Strength Tablets - Genapap® Gel-Coat Caplets® - Genebs® - Genebs® Extra Strength Caplets® - Genebs® Extra Strength Tablets - Goody's® Extra Strength Tablets - Goody's® Fast Pain Relief Tablets - Goody's® Headache Powders - Liquiprin® Drops - Roxicet® - Supac® - Tylenol® - Tylenol® Arthritis Pain Extended Relief Caplets® - Tylenol® Meltaways Children's - Tylenol® Concentrated Drops Infant's - Tylenol® Extra Strength Adult - 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Dehydrodolichyl diphosphate synthase Dehydrodolichyl diphosphate synthase is an enzyme that in humans is encoded by the DHDDS gene. # Function Dehydrodolichyl diphosphate (dedol-PP) synthase catalyzes cis-prenyl chain elongation to produce the polyprenyl backbone of dolichol, a glycosyl carrier lipid required for the biosynthesis of several classes of glycoproteins. # Clinical significance It has been suggested that missense mutations in the DHDDS gene are responsible for certain variants of retinitis pigmentosa. Since it is involved in the early steps of dolichol synthesis, vital e.g. for correct N-glycosylation, a disease caused by mutations in DHDDS should be considered a congenital disorder of glycosylation (and named DHDDS-CDG according to the novel nomenclature of CDGs). Many CDG subtypes present with retinitis pigmentosa as a major feature.

Zoledronic acid # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Zoledronic acid is a bisphosphonate that is FDA approved for the treatment of hypercalcemia of malignancy, multiple myeloma, bone metastases of solid tumors, osteoporosis,paget's disease, postmenopausal osteoporosis. Common adverse reactions include nausea, fatigue, anemia, bone pain, constipation, fever, vomiting, dyspnea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications Hypercalcemia of Malignancy Zoledronic acid Injection is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of greater than or equal to 12 mg/dL using the formula: cCa in mg/dL =Ca in mg/dL + 0.8 ( 4.0 g/dL – patient albumin ). Multiple Myeloma and Bone Metastases of Solid Tumors Zoledronic acid Injection is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. Important Limitation of Use The safety and efficacy of Zoledronic acid Injection in the treatment of hypercalcemia associated with hyperparathyroidism or with other nontumor-related conditions have not been established. # Dosage Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Hypercalcemia of Malignancy The maximum recommended dose of Zoledronic acid Injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL ) is 4 mg. The 4-mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive Zoledronic acid Injection should have serum creatinine assessed prior to each treatment. Dose adjustments of Zoledronic acid Injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 mcmol/L or less than 4.5 mg/dL). Patients should be adequately rehydrated prior to administration of Zoledronic acid Injection . Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of Zoledronic acid Injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia. Retreatment with Zoledronic acid Injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving Zoledronic acid Injection and serum creatinine must be assessed prior to retreatment with Zoledronic acid Injection. Multiple Myeloma and Metastatic Bone Lesions of Solid Tumors The recommended dose of Zoledronic acid Injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance (CrCl) greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known. Upon treatment initiation, the recommended Zoledronic acid Injection doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same area under the curve (AUC) as that achieved in patients with creatinine clearance of 75 mL/min. CrCl is calculated using the Cockcroft-Gault formula . During treatment, serum creatinine should be measured before each Zoledronic acid Injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows: For patients with normal baseline creatinine, increase of 0.5 mg/dL For patients with abnormal baseline creatinine, increase of 1.0 mg/dL In the clinical studies, Zoledronic acid Injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic acid Injection should be reinitiated at the same dose as that prior to treatment interruption. Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of Vitamin D daily. Preparation of Solution Zoledronic acid Injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer’s solution, and should be administered as a single intravenous solution in a line separate from all other drugs. 4 mg / 5 mL Single-Use Vial Vials of Zoledronic acid Injection concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection. To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the Zoledronic acid Injection concentrate from the vial for the dose required (see Table 2) The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP. If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C-8°C (36°F-46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours. # Dosage Forms and Strengths 4 mg/5 mL single-use vial of concentrate ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Zoledronic acid in adult patients. ### Non–Guideline-Supported Use # Indications - Monoclonal gammopathy of uncertain significance, with osteopenia or osteoporosis. - Osteopenia, secondary to androgen-deprivation therapy in prostate cancer patients; - Osteopenia, secondary to hormone therapy in breast cancer patients; - Osteopenia, secondary to ovarian dysfunction induced by adjuvant chemotherapy in premenopausal women with early-stage breast cancer; # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Zoledronic acid in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Zoledronic acid in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Zoledronic acid in pediatric patients. # Contraindications Hypersensitivity to Zoledronic Acid or Any Components of Zoledronic acid Injection Hypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported. # Warnings Drugs with Same Active Ingredient or in the Same Drug Class - Zoledronic acid Injection contains the same active ingredient as found in Reclast® (zoledronic acid). Patients being treated with Zoledronic acid Injection should not be treated with Reclast or other bisphosphonates. Hydration and Electrolyte Monitoring - Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of Zoledronic acid Injection. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with Zoledronic acid Injection in order to avoid hypocalcemia. Zoledronic acid Injection should be used with caution with other nephrotoxic drugs. - Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with Zoledronic acid Injection. If hypocalcemia hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary. Renal Impairment - Zoledronic acid Injection is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients with impaired renal function. Safety and pharmacokinetic data are limited in patients with severe renal impairment and the risk of renal deterioration is increased . Preexisting renal insufficiency and multiple cycles of Zoledronic acid Injection and other bisphosphonates are risk factors for subsequent renal deterioration with Zoledronic acid Injection. Factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible. - Zoledronic acid Injection treatment in patients with hypercalcemia of malignancy with severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine greater than 400 mcmol/L or greater than 4.5 mg/dL were excluded. - Zoledronic acid Injection treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine greater than 265 mcmol/L or greater than 3.0 mg/dL were excluded and there were only 8 of 564 patients treated with Zoledronic acid Injection 4 mg by 15-minute infusion with a baseline creatinine greater than 2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance less than 30 mL/min. Osteonecrosis of the Jaw - Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Zoledronic acid Injection. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis. - Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. - While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment. Musculoskeletal Pain - In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates, including Zoledronic acid Injection. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Atypical Subtrochanteric and Diaphyseal Femoral Fractures - Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including Zoledronic acid Injection. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to just above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. These fractures occur after minimal or no trauma. Patients may experience thigh or groin pain weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. A number of case reports noted that patients were also receiving treatment with glucocorticoids (such as prednisone or dexamethasone) at the time of fracture. Causality with bisphosphonate therapy has not been established. - Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain in the absence of trauma should be suspected of having an atypical fracture and should be evaluated. Discontinuation of Zoledronic acid Injection therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. It is unknown whether the risk of atypical femur fracture continues after stopping therapy. Patients with Asthma - While not observed in clinical trials with Zoledronic acid Injection, there have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates. Hepatic Impairment - Only limited clinical data are available for use of Zoledronic acid Injection to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely use Zoledronic acid Injection in these patients. Use in Pregnancy - Bisphosphonates, such as Zoledronic acid Injection, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. - Zoledronic acid Injection may cause fetal harm when administered to a pregnant woman. In reproductive studies in pregnant rats, subcutaneous doses equivalent to 2.4 or 4.8 times the human systemic exposure resulted in pre- and post-implantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. There are no adequate and well controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus . Hypocalcemia - Hypocalcemia has been reported in patients treated with Zoledronic acid Injection. Cardiac arrhythmias and neurologic adverse events (seizures, tetany, and numbness) have been reported secondary to cases of severe hypocalcemia. In some instances, hypocalcemia may be life-threatening. Hypocalcemia must be corrected before initiating Zoledronic acid Injection. Adequately supplement patients with calcium and vitamin D. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Hypercalcemia of Malignancy The safety of Zoledronic acid Injection was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either Zoledronic acid Injection 4 mg given as a 5-minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The population was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials. Renal Toxicity Administration of Zoledronic acid Injection 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zoledronic acid Injection 4 mg is given as a 15-minute intravenous infusion. Zoledronic acid Injection should be administered by intravenous infusion over no less than 15 minutes. The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 3). Table 3 provides adverse events that were reported by 10% or more of the 189 patients treated with Zoledronic acid Injection 4 mg or Pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumed causality to study drug. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Zoledronic acid in the drug label. # Drug Interactions In vitro studiesindicate that the plasma protein binding of zoledronic acid is low, with the unbound fraction ranging from 60% to77%. In vitrostudies also indicate that zoledronic acid does not inhibit microsomal CYP450 enzymes. In vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug. Aminoglycosides Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in Zoledronic acid Injection clinical trials. Loop Diuretics Caution should also be exercised when Zoledronic acid Injection is used in combination with loop diuretics due to an increased risk of hypocalcemia. Nephrotoxic Drugs Caution is indicated when Zoledronic acid Injection is used with other potentially nephrotoxic drugs. Thalidomide No dose adjustment for Zoledronic acid Injection 4 mg is needed when co-administered with thalidomide. In a pharmacokinetic study of 24 patients with multiple myeloma, Zoledronic acid Injection 4 mg given as a 15 minute infusion was administered either alone or with thalidomide (100 mg once daily on days 1-14 and 200 mg once daily on days 15-28). Co-administration of thalidomide with Zoledronic acid Injection did not significantly change the pharmacokinetics of Zoledronic acid or creatinine clearance. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category D - There are no adequate and well-controlled studies of Zoledronic acid Injection in pregnant women. Zoledronic acid Injection may cause fetal harm when administered to a pregnant woman. Bisphosphonates, such as Zoledronic acid Injection, are incorporated into the bone matrix and are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. If this drug is used during pregnancy or if the patient becomes pregnant while taking or after taking this drug, the patient should be apprised of the potential hazard to the fetus. - In female rats given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased in the mid- and high-dose groups (≥0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Adverse maternal effects were observed in all dose groups (with a systemic exposure of ≥0.07 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison) and included dystocia and periparturient mortality in pregnant rats allowed to deliver. Maternal mortality may have been related to drug-induced inhibition of skeletal calcium mobilization, resulting in periparturient hypocalcemia. This appears to be a bisphosphonate-class effect. - In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal effects were observed in the mid- and high-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). These adverse effects included increases in pre- and postimplantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects observed in the high-dose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the low-dose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dose group and included reduced body weights and food consumption, indicating that maximal exposure levels were achieved in this study. - In pregnant rabbits given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day during gestation (≤0.5 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas), no adverse fetal effects were observed. Maternal mortality and abortion occurred in all treatment groups (at doses ≥0.05 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zoledronic acid in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Zoledronic acid during labor and delivery. ### Nursing Mothers It is not known whether Zoledronic acid is excreted in human milk and because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Zoledronic acid Injection, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Zoledronic acid binds to bone long term and may be released over weeks to years. ### Pediatric Use - Zoledronic acid Injection is not indicated for use in children. - The safety and effectiveness of zoledronic acid was studied in a one-year, active-controlled trial of 152 pediatric subjects (74 receiving zoledronic acid). The enrolled population was subjects with severe osteogenesis imperfecta, aged 1-17 years, 55% male, 84% Caucasian, with a mean lumbar spine bone mineral density (BMD) of 0.431 gm/cm2, which is 2.7 standard deviations below the mean for age-matched controls (BMD Z-score of -2.7). At one year, increases in BMD were observed in the zoledronic acid treatment group. However, changes in BMD in individual patients with severe osteogenesis imperfecta did not necessarily correlate with the risk for fracture or the incidence or severity of chronic bone pain. The adverse events observed with Zoledronic acid Injection use in children did not raise any new safety findings beyond those previously seen in adults treated for hypercalcemia of malignancy. However, adverse reactions seen more commonly in pediatric patients included pyrexia (61%), arthralgia (26%), hypocalcemia (22%) and headache (22%). These reactions, excluding arthralgia, occurred most frequently within 3 days after the first infusion and became less common with repeat dosing. Because of long-term retention in bone, Zoledronic acid Injection should only be used in children if the potential benefit outweighs the potential risk. - Plasma zoledronic acid concentration data was obtained from 10 patients with severe osteogenesis imperfecta (4 in the age group of 3-8 years and 6 in the age group of 9-17 years) infused with 0.05 mg/kg dose over 30 min. Mean Cmax and AUC(0-last) was 167 ng/mL and 220 ngh/mL, respectively. The plasma concentration time profile of zoledronic acid in pediatric patients represent a multi-exponential decline, as observed in adult cancer patients at an approximately equivalent mg/kg dose. ### Geriatic Use Clinical studies of Zoledronic acid Injection in hypercalcemia of malignancy included 34 patients who were 65 years of age or older. No significant differences in response rate or adverse reactions were seen in geriatric patients receiving Zoledronic acid Injection as compared to younger patients. Because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function. ### Gender There is no FDA guidance on the use of Zoledronic acid with respect to specific gender populations. ### Race There is no FDA guidance on the use of Zoledronic acid with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Zoledronic acid in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Zoledronic acid in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Zoledronic acid in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Zoledronic acid in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous Method of Administration Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of Zoledronic acid Injection should not exceed 4 mg and the duration of infusion should be no less than 15 minutes. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial Zoledronic acid Injection dose. ### Monitoring There is limited information regarding Monitoring of Zoledronic acid in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Zoledronic acid in the drug label. # Overdosage - Clinical experience with acute overdosage of Zoledronic acid Injection is limited. Two patients received Zoledronic acid Injection 32 mg over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively. - In an open-label study of zoledronic acid 4 mg in breast cancer patients, a female patient received a single 48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episode of hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patient was discharged seven days after the overdose. - A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for a total dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increased GGT (nearly 100U/L, each value unknown). The outcome of this case is not known. - In controlled clinical trials, administration of Zoledronic acid Injection 4 mg as an intravenous infusion over 5 minutes has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minute intravenous infusion. In controlled clinical trials, Zoledronic acid Injection 8 mg has been shown to be associated with an increased risk of renal toxicity compared to Zoledronic acid Injection 4 mg, even when given as a 15-minute intravenous infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy. # Pharmacology ## Mechanism of Action The principal pharmacologic action of zoledronic acid is inhibition of bone resorption. Although the antiresorptive mechanism is not completely understood, several factors are thought to contribute to this action. In vitro, zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis. Zoledronic acid also blocks the osteoclastic resorption of mineralized bone and cartilage through its binding to bone. Zoledronic acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors. ## Structure - Zoledronic acid Injection contains zoledronic acid, a bisphosphonic acid which is an inhibitor of osteoclastic bone resorption. Zoledronic acid is designated chemically as (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate and its structural formula is: ## Pharmacodynamics - Clinical studies in patients with hypercalcemia of malignancy (HCM) showed that single-dose infusions of Zoledronic acid Injection are associated with decreases in serum calcium and phosphorus and increases in urinary calcium and phosphorus excretion. - Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying - pathophysiologic derangement in hypercalcemia of malignancy (HCM, tumor-induced hypercalcemia). Excessive release of calcium into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive dehydration and decreasing glomerular filtration rate. This, in turn, results in increased renal resorption of calcium, setting up a cycle of worsening systemic hypercalcemia. Reducing excessive bone resorption and maintaining adequate fluid administration are, therefore, essential to the management of hypercalcemia of malignancy. - Patients who have hypercalcemia of malignancy can generally be divided into two groups according to the pathophysiologic mechanism involved: humoral hypercalcemia and hypercalcemia due to tumor invasion of bone. In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors such as parathyroid hormone-related protein, which are elaborated by the tumor and circulate systemically. Humoral hypercalcemia usually occurs in squamous cell malignancies of the lung or head and neck or in genitourinary tumors such as renal cell carcinoma or ovarian cancer. Skeletal metastases may be absent or minimal in these patients. - Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products that stimulate bone resorption by osteoclasts. Tumors commonly associated with locally mediated hypercalcemia include breast cancer and multiple myeloma. - Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity of hypercalcemia, since concomitant hypoalbuminemia is commonly present. Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic conditions; however, these are not commonly or rapidly available in many clinical situations. Therefore, adjustment of the total serum calcium value for differences in albumin levels (corrected serum calcium, CSC) is often used in place of measurement of ionized calcium; several nomograms are in use for this type of calculation ## Pharmacokinetics Pharmacokinetic data in patients with hypercalcemia are not available. Distribution - Single or multiple (q 28 days) 5-minute or 15-minute infusions of 2, 4, 8 or 16 mg Zoledronic acid Injection were given to 64 patients with cancer and bone metastases. The postinfusion decline of zoledronic acid concentrations in plasma was consistent with a triphasic process showing a rapid decrease from peak concentrations at end of infusion to less than 1% of Cmax 24 hours postinfusion with population half-lives of t1/2α0.24 hours and t1/2β1.87 hours for the early disposition phases of the drug. The terminal elimination phase of zoledronic acid was prolonged, with very low concentrations in plasma between Days 2 and 28 postinfusion, and a terminal elimination half-life t 1/2⛛ of 146 hours. The area under the plasma concentration versus time curve (AUC0-24h) of zoledronic acid was dose proportional from 2-16 mg. The accumulation of zoledronic acid measured over three cycles was low, with mean AUC0-24h ratios for cycles 2 and 3 versus 1 of 1.13 ± 0.30 and 1.16 ± 0.36, respectively. - In vitroand ex vivo studies showed low affinity of zoledronic acid for the cellular components of human blood, with a mean blood to plasma concentration ratio of 0.59 in a concentration range of 30 ng/mL to 5000 ng/mL. In vitro, the plasma protein binding is low, with the unbound fraction ranging from 60% at 2 ng/mL to 77% at 2000 ng/mL of zoledronic acid. Metabolism - Zoledronic acid does not inhibit human P450 enzymes in vitro. Zoledronic acid does not undergo biotransformation in vivo. In animal studies, less than 3% of the administered intravenous dose was found in the feces, with the balance either recovered in the urine or taken up by bone, indicating that the drug is eliminated intact via the kidney. Following an intravenous dose of 20 nCi 14C-zoledronic acid in a patient with cancer and bone metastases, only a single radioactive species with chromatographic properties identical to those of parent drug was recovered in urine, which suggests that zoledronic acid is not metabolized. Excretion - In 64 patients with cancer and bone metastases, on average (± SD) 39 ± 16% of the administered zoledronic acid dose was recovered in the urine within 24 hours, with only trace amounts of drug found in urine post-Day 2. The cumulative percent of drug excreted in the urine over 0-24 hours was independent of dose. The balance of drug not recovered in urine over 0-24 hours, representing drug presumably bound to bone, is slowly released back into the systemic circulation, giving rise to the observed prolonged low plasma concentrations. The 0-24 hour renal clearance of zoledronic acid was 3.7 ± 2.0 L/h. - Zoledronic acid clearance was independent of dose but dependent upon the patient’s creatinine clearance. In a study in patients with cancer and bone metastases, increasing the infusion time of a 4-mg dose of zoledronic acid from 5 minutes (n=5) to 15 minutes (n=7) resulted in a 34% decrease in the zoledronic acid concentration at the end of the infusion ( 403 ± 118 ng/mL versus 264 ± 86 ng/mL) and a 10% increase in the total AUC (378 ± 116 ng x h/mL versus 420 ± 218 ng x h/mL). The difference between the AUC means was not statistically significant. ## Special Populations Pediatrics Zoledronic acid Injection is not indicated for use in children. Geriatrics - The pharmacokinetics of zoledronic acid were not affected by age in patients with cancer and bone metastases who ranged in age from 38 years to 84 years. Race - Population pharmacokinetic analyses did not indicate any differences in pharmacokinetics among Japanese and North American (Caucasian and African American) patients with cancer and bone metastases. Hepatic Insufficiency - No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of zoledronic acid. Renal Insufficiency - The pharmacokinetic studies conducted in 64 cancer patients represented typical clinical populations with normal to moderately impaired renal function. Compared to patients with normal renal function (N=37), patients with mild renal impairment (N=15) showed an average increase in plasma AUC of 15%, whereas patients with moderate renal impairment (N=11) showed an average increase in plasma AUC of 43%. Limited pharmacokinetic data are available for Zoledronic acid Injection in patients with severe renal impairment (creatinine clearance less than 30 mL/min). Based on population PK/PD modeling, the risk of renal deterioration appears to increase with AUC, which is doubled at a creatinine clearance of 10 mL/min. Creatinine clearance is calculated by the Cockcroft-Gault formula: CrCl= x weight (kg) {x 0.85 for female patients} - Zoledronic acid Injection systemic clearance in individual patients can be calculated from the population clearance of Zoledronic acid Injection, CL (L/h)=6.5(CrCl/90)0.4. These formulae can be used to predict the Zoledronic acid Injection AUC in patients, where CL = Dose/AUC0-∞. The average AUC0-24in patients with normal renal function was 0.42 mgh/L and the calculated AUC0-∞ for a patient with creatinine clearance of 75 mL/min was 0.66 mgh/L following a 4-mg dose of Zoledronic acid Injection. However, efficacy and safety of adjusted dosing based on these formulae have not been prospectively assessed ## Nonclinical Toxicology Carcinogenesis & Mutagenesis & Impairment Of Fertility - Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Mice were given oral doses of zoledronic acid of 0.1, 0.5, or 2.0 mg/kg/day. There was an increased incidence of Harderian gland adenomas in males and females in all treatment groups (at doses ≥0.002 times a human intravenous dose of 4 mg, based on a comparison of relative body surface areas). Rats were given oral doses of zoledronic acid of 0.1, 0.5, or 2.0 mg/kg/day. No increased incidence of tumors was observed (at doses ≤0.2 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas). - Zoledronic acid was not genotoxic in the Ames bacterial mutagenicity assay, in the Chinese hamster ovary cell assay, or in the Chinese hamster gene mutation assay, with or without metabolic activation. Zoledronic acid was not genotoxic in the in-vivo rat micronucleus assay. - Female rats were given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation. Effects observed in the high-dose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg, based on AUC comparison) included inhibition of ovulation and a decrease in the number of pregnant rats. Effects observed in both the mid-dose group (with systemic exposure of 0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison) and high-dose group included an increase in preimplantation losses and a decrease in the number of implantations and live fetuses. # Clinical Studies Hypercalcemia of Malignancy - Two identical multicenter, randomized, double-blind, double-dummy studies of Zoledronic acid Injection 4 mg given as a 5-minute intravenous infusion or pamidronate 90 mg given as a 2-hour intravenous infusion were conducted in 185 patients with hypercalcemia of malignancy (HCM). NOTE: Administration of Zoledronic acid Injection 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zoledronic acid Injection 4 mg is given as a 15-minute intravenous infusion. Zoledronic acid Injection should be administered by intravenous infusion over no less than 15 minutes .The treatment groups in the clinical studies were generally well balanced with regards to age, sex, race, and tumor types. The mean age of the study population was 59 years; 81% were Caucasian, 15% were Black, and 4% were of other races. 60% of the patients were male. The most common tumor types were lung, breast, head and neck, and renal. - In these studies, HCM was defined as a corrected serum calcium (CSC) concentration of greater than or equal to 12.0 mg/dL (3.00 mmol/L). The primary efficacy variable was the proportion of patients having a complete response, defined as the lowering of the CSC to less than or equal to 10.8 mg/dL (2.70 mmol/L) within 10 days after drug infusion. - To assess the effects of Zoledronic acid Injection versus those of pamidronate, the two multicenter HCM studies were combined in a preplanned analysis. The results of the primary analysis revealed that the proportion of patients that had normalization of corrected serum calcium by Day 10 were 88% and 70% for Zoledronic acid Injection 4 mg and pamidronate 90 mg, respectively (P=0.002) (see Figure 1). In these studies, no additional benefit was seen for Zoledronic acid Injection 8 mg over Zoledronic acid Injection 4 mg; however, the risk of renal toxicity of Zoledronic acid Injection 8 mg was significantly greater than that seen with Zoledronic acid Injection 4 mg. Secondary efficacy variables from the pooled HCM studies included the proportion of patients who had normalization of corrected serum calcium (CSC) by Day 4; the proportion of patients who had normalization of CSC by Day 7; time to relapse of HCM; and duration of complete response. Time to relapse of HCM was defined as the duration (in days) of normalization of serum calcium from study drug infusion until the last CSC value less than 11.6 mg/dL (less than 2.90 mmol/L). Patients who did not have a complete response were assigned a time to relapse of 0 days. Duration of complete response was defined as the duration (in days) from the occurrence of a complete response until the last CSC ≤10.8 mg/dL (2.70 mmol/L). The results of these secondary analyses for Zoledronic acid Injection 4 mg and pamidronate 90 mg are shown in Table 10. Clinical Trials in Multiple Myeloma and Bone Metastases of Solid Tumors Table 11 describes an overview of the efficacy population in three randomized Zoledronic acid Injection trials in patients with multiple myeloma and bone metastases of solid tumors. These trials included a pamidronate-controlled study in breast cancer and multiple myeloma, a placebo-controlled study in prostate cancer, and a placebo-controlled study in other solid tumors. The prostate cancer study required documentation of previous bone metastases and 3 consecutive rising PSAs while on hormonal therapy. The other placebo-controlled solid tumor study included patients with bone metastases from malignancies other than breast cancer and prostate cancer, including NSCLC, renal cell cancer, small cell lung cancer, colorectal cancer, bladder cancer, GI/genitourinary cancer, head and neck cancer, and others. These trials were comprised of a core phase and an extension phase. In the solid tumor, breast cancer and multiple myeloma trials, only the core phase was evaluated for efficacy as a high percentage of patients did not choose to participate in the extension phase. In the prostate cancer trials, both the core and extension phases were evaluated for efficacy showing the Zoledronic acid Injection effect during the first 15 months was maintained without decrement or improvement for another 9 months. The design of these clinical trials does not permit assessment of whether more than one-year administration of Zoledronic acid Injection is beneficial. The optimal duration of Zoledronic acid Injection administration is not known. The studies were amended twice because of renal toxicity. The Zoledronic acid Injection infusion duration was increased from 5 minutes to 15 minutes. After all patients had been accrued, but while dosing and follow-up continued, patients in the 8 mg Zoledronic acid Injection treatment arm were switched to 4 mg due to toxicity. Patients who were randomized to the Zoledronic acid Injection 8 mg group are not included in these analyses. Each study evaluated skeletal-related events (SREs), defined as any of the following: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. Change in antineoplastic therapy due to increased pain was a SRE in the prostate cancer study only. Planned analyses included the proportion of patients with a SRE during the study and time to the first SRE. Results for the two Zoledronic acid Injection placebo-controlled studies are given in Table 12. In the breast cancer and myeloma trial, efficacy was determined by a noninferiority analysis comparing Zoledronic acid Injection to pamidronate 90 mg for the proportion of patients with a SRE. This analysis required an estimation of pamidronate efficacy. Historical data from 1,128 patients in three pamidronate placebo-controlled trials demonstrated that pamidronate decreased the proportion of patients with a SRE by 13.1% (95% CI = 7.3%, 18.9%). Results of the comparison of treatment with Zoledronic acid Injection compared to pamidronate are given in Table 13. # How Supplied Zoledronic Acid Injection 4 mg/5 mL single-use vial of concentrate Carton of 1 vial………………………………………………NDC 68083-116-01 ## Storage Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be instructed to tell their doctor if they have kidney problems before being given Zoledronic acid Injection. - Patients should be informed of the importance of getting their blood tests (serum creatinine) during the course of their Zoledronic acid Injection therapy. - Zoledronic acid Injection should not be given if the patient is pregnant or plans to become pregnant, or if she is breast-feeding. - Patients should be advised to have a dental examination prior to treatment with Zoledronic acid Injection and should avoid invasive dental procedures during treatment. - Patients should be informed of the importance of good dental hygiene and routine dental care. - Patients with multiple myeloma and bone metastasis of solid tumors should be advised to take an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of Vitamin D daily. - Patients should be advised to report any thigh, hip or groin pain. It is unknown whether the risk of atypical femur fracture continues after stopping therapy. - Patients should be aware of the most common side effects including: anemia, nausea, vomiting, constipation, diarrhea, fatigue, fever, weakness, lower limb edema, anorexia, decreased weight, bone pain, myalgia, arthralgia, back pain, malignant neoplasm aggravated, headache, dizziness, insomnia, paresthesia, dyspnea, cough, and abdominal pain. - There have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates, including Zoledronic acid. Before being given Zoledronic acid, patients should tell their doctor if they are aspirin-sensitive. # Precautions with Alcohol - Alcohol-Zoledronic acid interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ZOLEDRONIC ACID ® # Look-Alike Drug Names There is limited information regarding Zoledronic acid Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price

GLUT2 Glucose transporter 2 (GLUT2) also known as solute carrier family 2 (facilitated glucose transporter), member 2 (SLC2A2) is a transmembrane carrier protein that enables protein facilitated glucose movement across cell membranes. It is the principal transporter for transfer of glucose between liver and blood, and has a role in renal glucose reabsorption. It is also capable of transporting fructose. Unlike GLUT4, it does not rely on insulin for facilitated diffusion. In humans, this protein is encoded by the SLC2A2 gene. # Tissue distribution GLUT2 is found in cellular membranes of: - liver (Primary) - pancreatic β cell (Primary) - hypothalamus (Not overly significant) - basolateral membrane of small intestine and apical GLUT2 is also suggested. - basolateral membrane of renal tubular cells # Function GLUT2 has high capacity for glucose but low affinity (high Km, ca. 15-20 mM) and thus functions as part of the "glucose sensor" in the pancreatic β-cells of rodents, though in human β-cells the role of GLUT2 seems to be a minor one. It is a very efficient carrier for glucose. GLUT2 also carries glucosamine. When the glucose concentration in the lumen of the small intestine goes above 30 mM, such as occurs in the fed-state, GLUT2 is up-regulated at the brush border membrane, enhancing the capacity of glucose transport. Basolateral GLUT2 in enterocytes also aids in the transport of fructose into the bloodstream through glucose-dependent cotransport. # Clinical significance Defects in the SLC2A2 gene are associated with a particular type of glycogen storage disease called Fanconi-Bickel syndrome. In drug-treated diabetic pregnancies in which glucose levels in the woman are uncontrolled, neural tube and cardiac defects in the early-developing brain, spine, and heart depend upon functional GLUT2 carriers, and defects in the GLUT2 gene have been shown to be protective against such defects in rats. However, whilst a lack of GLUT2 adaptability is negative, it is important to remember the fact that the main result of untreated gestational diabetes appears to cause babies to be of above-average size, which may well be an advantage that is managed very well with a healthy GLUT2 status. Maintaining a regulated osmotic balance of sugar concentration between the blood circulation and the interstitial spaces is critical in some cases of edema including cerebral edema. GLUT2 appears to be particularly important to osmoregulation, and preventing edema-induced stroke, transient ischemic attack or coma, especially when blood glucose concentration is above average. GLUT2 could reasonably be referred to as the "diabetic glucose transporter" or a "stress hyperglycemia glucose transporter." # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

Malignant tumours of the salivary glands Malignant tumours of the salivary glands are relatively rare, with an estimated incidence of less than 1 per 100 000. They represent a little less than 5% of head and neck tumours. These are generally slow-growing tumours of varied histology, long doubling times and late locoregional and distant recurrences. Prolonged survival is possible, even with metastatic disease.These recommendations do not consider salivary gland lymphomas. They were validated in August 1999 and an update is planned for the year 2000.PROGNOSTIC FACTORSThe most important prognostic factors with respect to local control and survival are tumour size and clinical stage. Other independent factors are the histology, (low grade vs high grade) and the treatment (the quality of the surgical excision). Knowledge of these factors is part of initial staging, and allows the subsequent therapeutic strategy to be matched to the clinical situation. ## Diagnosis and staging Standard staging of malignant tumours of the salivary glands is based on clinical examination, imaging and histopathological examination. From clinical examination, the size of the lesion, locoregional extension, and any signs suggestive of malignancy (e.g. facial paralysis, trismus, cutaneous infiltration) can be determined. Endoscopic examination (often under general anaesthesia) is required to obtain biopsy samples and to complete the staging of tumours of the minor salivary glands (notably those in the pharynx and larynx). Clinical assessment of locoregional extension is based on examination of the neck. A total body examination is required to look for distant metastases. An assessment of performance status, nutritional status and of major organ function, using clinical and laboratory parameters, determines whether or not the patient has operable disease (standard). Standard imaging consists of a cervico-facial CT scan or highresolution ultrasound (level of evidence B). High-resolution ultrasonography must only be used by those teams trained in this method. For tumours under the maxilla, an orthopantogram is necessary to complete staging (standard). MRI imaging and sialograms are options. Further imaging is done according to symptoms and signs suggestive of malignant involvement and extraglandular spread. Histopathological examination is necessary to confirm a diagnosis of malignancy. An excision biopsy with frozen section is required for the major salivary glands (standard) and a simple biopsy for the minor salivary glands (standard). A preoperative diagnosis can be made by cytological analysis following fineneedle aspiration (option). ## Staging The TNM AJC/UICC classification is the most practical and the best adapted to treatment decision-making (standard). The histological classification differentiating the tumours according to grade (low vs high grade), is now universally recognized (standard). ## Treatment The basic treatment of salivary gland tumours is complete surgical excision (standard), with or without postoperative irradiation, according to the clinical stage and the histological grade. The combination of surgery and radiotherapy is the treatment of choice for high grade disease. Routine postoperative radiotherapy is indicated for stage II, III and IV high grade tumours and for low grade stage III and IV tumours (standard). It is also indicated in all cases in which surgery has been macro-or microscopically incomplete (standard). Neutron therapy alone, when possible, is the treatment of choice for inoperable tumours, whatever the stage and grade. To a lesser degree, neutron therapy provides an alternative treatment for locally advanced disease (stages III and IV) where surgery is likely to be difficult or to result in significant functional sequelae (option). This requires further evaluation. Postoperative neutron therapy is not indicated except in the case of large-volume residual disease (option, level of evidence C). The place of chemotherapy remains unclear. It should only be given within a multicentre therapeutic trial. Treatment is according to clinical stage and histological grade. ## Stage i, low grade / high grade: t1a t2a n0 m0 Complete surgical resection is the standard treatment for stage I tumours of the salivary glands . For tumours of the major salivary glands the gland must be completely excised (standard). For tumours of the minor salivary glands, a wide radical resection must be undertaken (standard). In all cases, the excision should be complete and in the case of encapsulated tumours, outside the capsule. If the resection is macroscopically and microscopically complete, there is no indication for adjuvant radiotherapy, even for high grade tumours (standard). If the excision is incomplete, or if histological examination has shown tumour at the excision margins, postoperative radiotherapy is indicated (standard). Postoperative irradiation should be with photons (±electrons) with standard fractionation (level of evidence A). Irradiation with neutrons can be given in cases of large-volume residual disease (option, level of evidence C). Routine ipsilateral nodal clearance is standard for T2 high grade tumours (standard, level of evidence B) and is an option for T1a tumours (option). If nodal involvement is detected at the time of surgery, ipsilateral neck dissection followed by routine postoperative radiotherapy is recommended (level of evidence B). ## Stage ii, t1b t2b t3a n0 m0 Low grade tumours Surgery alone, of variable extent, is the standard treatment [fig_ref] Figure 3: Treatment of stage II disease [/fig_ref]. If a complete resection is likely to result in a significant functional or cosmetic deficit, neutron therapy alone can be undertaken (option, level of evidence C). Postoperative radiotherapy must be undertaken if the surgical excision margins are involved (standard). In the case of positive nodes, extended surgical excision of the tumour and cervical nodes is followed by postoperative irradiation irrespective of whether the resection is macroscopically or microscopically complete (level of evidence B) or incomplete (level of evidence A). ## High grade tumours Surgery alone (complete excision, with or without subsequent extraglandular extension and ipsilateral neck dissection) is indicated for lesions limited to the gland (standard) . In the case of extension of the tumour to involve the facial nerve or crucial structures, the therapeutic options are extensive disfiguring surgery or neutron therapy alone. External irradiation (with neutrons) as first-line therapy can be considered for lesions judged to be incompletely resectable, or where extensive disfiguring surgery will be necessary with the risk of significant functional impairment (notably disease extending to the facial nerve, infratemporal fossa or the mandible) (option, level of evidence B). Routine postoperative external irradiation to tumour and nodes is standard when the excision has been incomplete (macro-and microscopically) or in the case of positive nodes (standard). It is recommended in cases of complete excision (option, level of evidence B). The role of chemotherapy, either as neoadjuvant or adjuvant treatment or with the aim of radiosensitization, must be evaluated in prospective therapeutic trials (it has no role as routine treatment). ## Stage iii, t3b t4a n0 m0 all t (except t4b) n1 m0 Low grade tumours Low grade stage III tumours are treated in the same way as high grade stage II tumours . If surgery has been complete, postoperative irradiation to the tumour and nodes remains the standard treatment. Neutron therapy alone is preferable in certain cases where surgery would be very extensive and disfiguring. The standard treatment of N1 lesions is primary tumour and nodal surgery with uni-or bilateral neck dissection (bilateral in the case of midline tumours), followed by postoperative irradiation (standard). The extent of nodal irradiation will depend on the histological findings following neck dissection. ## High grade tumours For stage III high grade tumours, two types of treatment can be considered: complete excision of the primary tumour and nodes, followed by radiotherapy, or neutron therapy alone to both tumour and nodes (option) . The place of chemotherapy must be evaluated within prospective trials (it has no role as routine treatment). ## Stage iv disease T4b low and high grade, all N, M0 There is no standard therapeutic approach for the management of patients presenting with stage 4b low or high grade node-positive stage IV disease . The therapeutic options are neutron therapy alone to tumour and nodes or extensive disfiguring surgery followed by radiotherapy (level of evidence B). Surgery should be radical and carried out by cancer specialists. The role of chemotherapy remains to be evaluated within prospective therapeutic trials. For T4b N0 M0 disease, neutron therapy alone is the technique of choice (level of evidence B). The role of chemotherapy must be evaluated within prospective therapeutic trials (no role in routine use). ## All t, n2 or n3 m0 disease If the primary lesion is easily resectable (T1-T2), the standard treatment is surgical excision of tumour and nodes. In all other cases, neutron therapy alone, when possible, is preferable to extensive disfiguring surgery (option) . ## All t, all n, m1 disease (distant metastases) In metastatic disease, the recommended therapeutic approach is palliative treatment (standard) and the evaluation of chemotherapy and/or surgery and/or radiotherapy within multicentre trials (option) . Elective surgical excision is the standard treatment for isolated pulmonary metastases. ## Inoperable disease In patients unfit for surgery, or with unresectable disease, the recommended treatment is neutron therapy alone where possible (option, level of evidence B) . Standard radiotherapy with photons, including those protocols using hyperfractionation or accelerated irradiation (which is still under evaluation in this condition) gives inferior results (level of evidence B). Incomplete surgery followed by radiotherapy with photons, is not recommended. The place of chemotherapy, especially in high grade tumours, must be evaluated within prospective trials. ## Loco-regional recurrence There is no standard therapeutic approach. This will depend largely on the type of recurrence and above all on the treatment that has previously been given to the primary tumour. In the case of relapse after surgery, further surgery followed by postoperative radiotherapy, or neutron therapy alone can be considered (options). For recurrent disease after radiotherapy alone or after surgery followed by radiotherapy, the treatment options are: repeat surgery if possible, neutron therapy at a dose limited by the previous irradiation, or chemotherapy within a prospective trial (especially for high grade disease) . For nodal relapses, uni-or bilateral nodal dissection (± postoperative irradiation), can be considered (options). If the recurrence is inoperable, neutron therapy alone, irradiation with photons combined with localized hyperthermia, or chemotherapy within a prospective trial (especially for high grade disease) are the treatment options. ## Follow-up Monthly surveillance is recommended during the first 6 months following treatment (3 months in the case of low grade tumours and stage I and II disease). Thereafter, follow-up can be 4-monthly, then 6-monthly for 3-4 years, then annually. The assessment should include a chest X-ray (AP and lateral) every 6 months initially, then every year. ## Internal reviewers C Alzieu (Institut Paoli Calmettes, Marseille), P Barrellier (Centre François Baclesse, Caen), G Dolivet (Centre Alexis Vautrin, Options · radical surgery followed by radiotherapy to tumour and nodes · neutron therapy alone to tumour and nodes · chemotherapy within a clinical trial Follow-up [fig] Figure 1, Figure 2: Treatment of stage I carcinoma of the salivary glands (low grade) Treatment of stage I disease (high grade) [/fig] [fig] Figure 3: Treatment of stage II disease (low grade) [/fig] [fig] Figure 6, Figure 7: Treatment · radiotherapy for palliation or tumour reduction · cytoreduction surgery · chemotherapy (high grade tumours) Treatment of stage IV metastatic disease [/fig]

Obtaining venous and arterial access # Anatomy of the Femoral Triangle The femoral triangle of Scarpa is an anatomical region of the upper inner human thigh. ## Boundaries It is bounded by: - the inguinal ligament superiorly - the sartorius muscle laterally - the adductor longus muscle medially - Its floor is formed by the iliopsoas and pectineus. - Its roof is formed by the fascia lata. - The left femoral triangle - The right femoral triangle - The bifurcation of the femoral artery generally lies distal to the middle third of the femoral head, and the site of arterial puncture should lie above this (click to enlarge) # Contents It is important as a number of vital structures pass through it, right under the skin - most notably (from lateral to medial): - the femoral nerve - the femoral artery - the femoral vein it also contains the deep inguinal nodes. # Mnemonics Several mnemonics have been created to remember the order of the nerve, artery, and vein in this triangle: - lateral to medial - "NAVEL" nerve, artery, vein, empty space, lymphatics. - medial to lateral - "VAN": vein, artery, nerve. These three structures are found in the same order in the intercostal space, from top to bottom. - medial to lateral - "vagina, artery, nerve" - the phrase "venous near the penis" can be used to remember that the vein is more medial than the artery or nerve. # Identification of Landmarks for Access ## Femoral Access: The right or left femoral arteries are the most commonly used access sites for coronary arteriography. The common femoral artery courses medially to the femoral head and the bifurcation of the common femoral artery into its branches is generally distal to the middle third of the femoral head, which can be localized by fluoroscopy before arterial puncture. The anterior wall of the common femoral artery should be punctured several centimeters below the inguinal ligament but proximal to the bifurcation of the superficial femoral and profunda arterial branches. If the puncture site is proximal to the inguinal ligament, hemostasis after the procedure may be difficult with manual compression, leading to an increased risk of retroperitoneal hemorrhage. If the puncture site is at or distal to the femoral bifurcation, there is a higher risk of pseudoaneurysm formation after sheath removal. Ipsilateral cannulation of the femoral artery and femoral vein also increases the risk of arteriovenous fistula formation. Calcification of the femoral artery may also be present which may guide in placement of the arterial and venous sheaths. ## Radial and Brachial Access: Although Sones first introduced the cutdown approach to the brachial artery for coronary arteriography, access to the brachial and radial arteries is now most often obtained percutaneously. These approaches are preferred to the femoral approach in the presence of severe peripheral vascular disease and morbid obesity (1, 2), and radial artery access is generally preferred to brachial catheterization due to its ease of catheter entry and removal (3). Systemic anticoagulation with intravenous heparin or bivalirudin is used for both approaches to prevent catheter thrombosis. The radial artery approach allows immediate ambulation after coronary arteriography with lower cost (compared with femoral closure devices) and improved coronary visualization (compared with smaller 4F diameter femoral catheters) (4). The radial approach relies upon the use of smaller guiding catheters. In addition, these approach to the coronary ostium is from the right, rather than from the left via the aortic arch with the femoral approach, and this may present a challenge in cannulating the coronary arteries. Support may be reduced as a result of smaller guiding catheter equipment. Arterial spasm and variable anatomy in the arm and the subclavian arteries may pose obstacles. SVGs can be engaged using either brachial or radial artery, but cannulation of the internal mammary artery (IMA) is best performed from the left brachial or radial artery. Engagement of the left IMA from the right brachial or radial artery is technically challenging but may be performed using a “headhunter” or another shaped catheter for selective entry into the left subclavian artery. A 0.035-inch angled hydrophilic guidewire is the most useful support wire for access to the subclavian artery. Special Considerations Regarding Catheter Selection: The brachial artery easily accommodates an 8F (1 French = 0.33mm in diameter) sheath, whereas the radial artery is smaller and generally limited to 5 to 7F catheters. Before radial artery access is attempted, an Allen test should be carried out to ensure that the ulnar artery is patent in the event of radial artery occlusion (5). # Local Subcutaneous Anesthetic Administration Initially, Lidocaine should be administered subcutaneously with a small gauge needle (25 gauge). The patient should be warned before the needle is inserted. Two small blebs are then raised at the two sites where the skin will be punctured (the venous insertion site and the arterial insertion site). These two blebs should be approximately 1 cm apart from each other. The skin should be rubbed after the Lidocaine has been inserted to facilitate the entry of the anesthetic throughout the subcutaneous tissue. If possible, a brief time should lapse before the deeper anesthetic is administered. A larger 21 gauge needle is then used to administer Lidocaine more deeply. The patient should be told that they may feel a sensation of burning with this deep Lidocaine administration. Attempts should not be made to enter the artery with the needle used for injection. Indeed, before each deep injection is made, the operator should pull backwards on the syringe to assure that a Lidocaine injection is not being made directly into the vein or the artery. Direct administration of a bolus of Lidocaine into the arterial or venous system could result in Lidocaine toxicity. # Cannulation of the Artery: Equipment and Technique For right handed operators, the pulse should be palpated with the left hand, and the cannula should be held in the right hand. Some operators will puncture between the two fingers that are palpating the pulse. Other operators puncture below the two fingers palpating the pulse. The bevel of the canula should be pointing up so that the wire can freely move antegrade when it enters the vessel. There are two ways to access the arterial system: ## The Single Wall Puncture Technique: In this technique, only the front wall of the artery is punctured. The benefit of this technique is the potential to limit bleeding complications. A single wall needle is also called a thin wall needle. It does not have a stylet. When puncturing with this needle, advance the needle until you get blood return. - Single wall puncture needle without a stylet. - The needle is advanced until the lumen is entered and blood flows from cannula. - With bevel up, insert wire into lumen. No resistance should be encountered. ## The Double Wall Puncture or Seldinger Technique: In this technique, both the front and the the back walls of the artery are punctured. Once the needle is advanced deeply to puncture both walls, remove the stylet and pull back on the needle until you get blood return. With the bevel facing up, insert the wire antegrade. There should be no resistance. Next, pull the needle out of the artery and wipe the blood from the wire. You can then advance the sheath or the catheter in over the wire. - Seldinger or Double Wall Needle with Sylet - Insert needle through both anterior & posterior wall of artery. - Remove stylet, withdraw needle until blood flows from cannula - With bevel up, insert wire into lumen. No resistance should be encountered Both the single wall and double wall needles are usually 18 gauge. Source of pictures: # 2011 ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention (DO NOT EDIT) ## Vascular Access (DO NOT EDIT)

Zestoretic overdose # Overdosage topics General Lisinopril Hydrochlorothiazide ## General No specific information is available on the treatment of -verdosage with ZESTORETIC. Treatment is symptomatic and supportive. Therapy with ZESTORETIC should be discontinued and the patient observed closely. Suggested measures include induction of emesis and/or gastric lavage, and correction of dehydration, electrolyte imbalance and hypotension by established procedures. Return to top ## Lisinopril Following a single oral dose of 20 g/kg no lethality occurred in rats and death occurred in one of 20 mice receiving the same dose. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. Lisinopril can be removed by hemodialysis. Return to top ## Hydrochlorothiazide Oral administration of a single oral dose of 10 g/kg to mice and rats was not lethal. The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. Return to top Adapted from the FDA Package Insert.

Separase Separase, also known as separin, is a cysteine protease responsible for triggering anaphase by hydrolysing cohesin, which is the protein responsible for binding sister chromatids during the early stage of anaphase. In humans, separin is encoded by the ESPL1 gene. # Discovery In S. cerevisiae, separase is encoded by the esp1 gene. Esp1 was discovered by Kim Nasmyth and coworkers in 1998. # Function Stable cohesion between sister chromatids before anaphase and their timely separation during anaphase are critical for cell division and chromosome inheritance. In vertebrates, sister chromatid cohesion is released in 2 steps via distinct mechanisms. The first step involves phosphorylation of STAG1 or STAG2 in the cohesin complex. The second step involves cleavage of the cohesin subunit SCC1 (RAD21) by separase, which initiates the final separation of sister chromatids. In S. cerevisiae, Esp1 is coded by ESP1 and is regulated by the securin Pds1. The two sister chromatids are initially bound together by the cohesin complex until the beginning of anaphase, at which point the mitotic spindle pulls the two sister chromatids apart, leaving each of the two daughter cells with an equivalent number of sister chromatids. The proteins that bind the two sister chromatids, disallowing any premature sister chromatid separation, are a part of the cohesin protein family. One of these cohesin proteins crucial for sister chromatid cohesion is Scc1. Esp1 is a separase protein that cleaves the cohesin subunit Scc1 (RAD21), allowing sister chromatids to separate at the onset of anaphase during mitosis. # Regulation When the cell is not dividing, separase is prevented from cleaving cohesin through its association with another protein, securin, as well as phosphorylation by the cyclin-CDK complex. This provides two layers of negative regulation to prevent inappropriate cohesin cleavage. Note that separase cannot function without initially forming the securin-separase complex in most organisms. This is because securin helps properly fold separase into the functional conformation. However, yeast does not appear to require securin to form functional separase because anaphase occurs in yeast even with a securin deletion. On the signal for anaphase, securin is ubiquitinated and hydrolysed, releasing separase for dephosphorylation by the APC-Cdc20 complex. Active separase can then cleave Scc1 for release of the sister chromatids. Separase initiates the activation of Cdc14 in early anaphase and Cdc14 has been found to dephosphorylate securin, thereby increasing its efficiency as a substrate for degradation. The presence of this positive feedback loop offers a potential mechanism for giving anaphase a more switch-like behavior.

IMITREX injection overdosage # Overdosage No gross overdoses in clinical practice have been reported. Coronary vasospasm was observed after intravenous administration of IMITREX Injection . Overdoses would be expected from animal data (dogs at 0.1 g/kg, rats at 2 g/kg) to possibly cause convulsions, tremor, inactivity, erythema of the extremities, reduced respiratory rate, cyanosis, ataxia, mydriasis, injection site reactions (desquamation, hair loss, and scab formation), and paralysis. The elimination half-life of sumatriptan is about 2 hours , and therefore monitoring of patients after overdose with IMITREX Injection should continue for at least 10 hours or while symptoms or signs persist. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.

Brucella # Overview Human brucellosis is caused by four Brucellae species: B. abortus, B. canis, B. melitensis, and B. suis. # Causes - Brucella is a genus of gram-negative bacteria.They are small (0.5 to 0.7 by 0.6 to 1.5 µm), non-motile and encapsulated coccobacilli. ## Brucella species Brucella species have been found primarily in mammals. Brucellla species, with their host and degree of virulence is described below: ## Tests to differentiate brucella species Following tests may be used to differentiate between the different species of brucella.

Crotamiton # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Crotamiton is a pesticide that is FDA approved for the treatment of scabies (sarcoptes scabiei) and for symptomatic treatment of pruritic skin. Common adverse reactions include dermatitis, skin irritation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - For eradication of scabies (Sarcoptes scabiei) and for symptomatic treatment of pruritic skin. - Dosing Information - Massage gently into affected areas until medication is completely absorbed. Repeat as needed. - LOTION: Shake well before using. - Dosing Information - Thoroughly massage into the skin of the whole body from the chin down, paying particular attention to all folds and creases. A second application is advisable 24 hours later. Clothing and bed linen should be changed the next morning. A cleansing bath should be taken 48 hours after the last application. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Crotamiton in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Dosage # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Crotamiton FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Crotamiton in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Crotamiton in pediatric patients. # Contraindications - Eurax should not be applied topically to patients who develop a sensitivity or are allergic to it or who manifest a primary irritation response to topical medications. # Warnings - If severe irritation or sensitization develops, treatment with this product should be discontinued and appropriate therapy instituted. ### Precautions General - Eurax should not be applied in the eyes or mouth because it may cause irritation. It should not be applied to acutely inflamed skin or raw or weeping surfaces until the acute inflammation has subsided. # Adverse Reactions ## Clinical Trials Experience - Primary irritation reactions, such as dermatitis, pruritus, and rash, and allergic sensitivity reactions have been reported in a few patients. ## Postmarketing Experience There is limited information regarding Crotamiton Postmarketing Experience in the drug label. # Drug Interactions - None known. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Animal reproduction studies have not been conducted with Eurax. It is also not known whether Eurax can cause fetal harm when applied topically to a pregnant woman or can affect reproduction capacity. Eurax should be given to a pregnant woman only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Crotamiton in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Crotamiton during labor and delivery. ### Nursing Mothers - There is no FDA guidance on the use of Crotamiton with respect to nursing mothers. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Clinical studies with Eurax (crotamiton USP) Lotion/Cream did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender - There is no FDA guidance on the use of Crotamiton with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Crotamiton with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Crotamiton in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Crotamiton in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Crotamiton in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Crotamiton in patients who are immunocompromised. # Administration and Monitoring ### Administration - In Scabies: Thoroughly massage into the skin of the whole body from the chin down, paying particular attention to all folds and creases. A second application is advisable 24 hours later. Clothing and bed linen should be changed the next morning. A cleansing bath should be taken 48 hours after the last application. - In Pruritus: Massage gently into affected areas until medication is completely absorbed. Repeat as needed. - LOTION: Shake well before using. DIRECTIONS FOR PATIENTS WITH SCABIES: - Take a routine bath or shower. Thoroughly massage Eurax cream or lotion into the skin from the chin to the toes including folds and creases. - Put Eurax cream or lotion under fingernails after trimming the fingernails short, because scabies are very likely to remain there. A toothbrush can be used to apply the Eurax cream or lotion under the fingernails. Immediately after use, the toothbrush should be wrapped in paper and thrown away. *Use of the same brush in the mouth could lead to poisoning. - A second application is advisable 24 hours later. - A 60 gram tube or bottle is sufficient for two applications. - Clothing and bed linen should be changed the next day. Contaminated clothing and bed linen may be dry-cleaned, or washed in the hot cycle of the washing machine. - A cleansing bath should be taken 48 hours after the last application ### Monitoring - There is limited information regarding Monitoring of Crotamiton in the drug label. - Description # IV Compatibility - There is limited information regarding IV Compatibility of Crotamiton in the drug label. # Overdosage - There is no specific information on the effect of overtreatment with repeated topical applications in humans. A death was reported but cause was not confirmed. - Accidental oral ingestion may be accompanied by burning sensation in the mouth, irritation of the buccal, esophageal and gastric mucosa, nausea, vomiting, abdominal pain. - If accidental ingestion occurs, call your Poison Control Center. # Pharmacology ## Mechanism of Action - Eurax has scabicidal and antipruritic actions. The mechanisms of these actions are not known. ## Structure - Eurax (crotamiton USP) is a scabicidal and antipruritic agent available as a cream or lotion for topical use only. Eurax provides 10% (w/w) of the synthetic, crotamiton USP, in a vanishing-cream or emollient-lotion base containing: carbomer-934, cetyl alcohol, diazolidinylurea, dimethicone, fragrance, laureth-23, magnesium aluminum silicate, magnesium nitrate, methylchloroisothiazolinone, methylisothiazolinone, petrolatum, propylene glycol, sodium hydroxide, steareth-2, and water. In addition, the cream contains glyceryl stearate. - Crotamiton is N-ethyl-N-(o-methylphenyl)-2-butenamide and its structural formula is: - Crotamiton USP is a colorless to slightly yellowish oil, having a faint amine-like odor. It is miscible with alcohol and with methanol. Crotamiton is a mixture of the cis and trans isomers. Its molecular weight is 203.28. ## Pharmacodynamics There is limited information regarding Crotamiton Pharmacodynamics in the drug label. ## Pharmacokinetics - The pharmacokinetics of crotamiton and its degree of systemic absorption following topical application have not been determined. ## Nonclinical Toxicology Carcinogenesis and Mutagenesis and Impairment of Fertility - Long-term carcinogenicity studies in animals have not been conducted. # Clinical Studies - There is limited information regarding Clinical Studies of Crotamiton in the drug label. # How Supplied Eurax® (crotamiton USP) - Cream: 60 g tubes NDC 10631-091-60 (NSN 6505-00-116-0200) - Lotion: 60 g (2 oz.) bottles NDC 10631-092-60 (NSN 6505-01-153-4423) - 454 g (16 oz.) bottles NDC 10631-092-16 - SHAKE WELL before using. ## Storage - Store at room temperature. - Keep out of reach of children. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information DIRECTIONS FOR PATIENTS WITH SCABIES: - Take a routine bath or shower. Thoroughly massage Eurax cream or lotion into the skin from the chin to the toes including folds and creases. - Put Eurax cream or lotion under fingernails after trimming the fingernails short, because scabies are very likely to remain there. A toothbrush can be used to apply the Eurax cream or lotion under the fingernails. Immediately after use, the toothbrush should be wrapped in paper and thrown away. *Use of the same brush in the mouth could lead to poisoning. - A second application is advisable 24 hours later. - A 60 gram tube or bottle is sufficient for two applications. - Clothing and bed linen should be changed the next day. Contaminated clothing and bed linen may be dry-cleaned, or washed in the hot cycle of the washing machine. - A cleansing bath should be taken 48 hours after the last application # Precautions with Alcohol - Alcohol-Crotamiton interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Eurax # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price

Heller myotomy Heller myotomy is a surgical procedure in which the muscles of the cardia (lower esophageal sphincter or LES) are cut, allowing food and liquids to pass to the stomach. It is used to treat achalasia, a disorder in which the lower esophageal sphincter fails to relax properly, making it difficult for food and liquids to reach the stomach. It was first performed by Ernest Heller in 1913. Then and until recently, this surgery was performed using an open procedure, either through the chest (thoracotomy) or through the abdomen (laparotomy). However, open procedures involve greater risks and longer recovery times. Modern Heller myotomy is normally performed using minimally invasive laparoscopic techniques, which minimize risks and speed recovery significantly. During the procedure, the patient is put under general anesthesia. Five or six small incisions are made in the abdominal wall and laparoscopic instruments are inserted. The myotomy is a lengthwise cut along the esophagus, starting above the LES and extending down onto the stomach a little way. The esophagus is made of several layers, and the myotomy only cuts through the outside muscle layers which are squeezing it shut, leaving the inner muscosal layer intact. There is a small risk of perforation during the myotomy. A barium swallow is performed after the surgery to check for leaks. If the surgeon accidentally cuts through the innermost layer of the esophagus, the perforation may need to be closed with a stitch. Food can easily pass downward after the myotomy has cut through the lower esophageal sphincter, but stomach acids can also easily reflux upward. Therefore, this surgery is often combined with partial fundoplication to reduce the incidence of postoperative acid reflux. In Dor or anterior fundoplication, which is the most common method, the fundus of the stomach is wrapped over the front of the esophagus and stitched into place. In Toupet or posterior fundoplication, the fundus is passed around the back of the esophagus instead. Nissen or complete fundoplication (wrapping the stomach all the way around the esophagus) is generally not considered advisable because peristalsis is absent in achalasia patients. This is a somewhat challenging operation, and surgeons have reported improved outcomes after their first 50 patients. After laparoscopic surgery, most patients can take clear liquids later the same day, start a soft diet within 2-3 days, and return to a normal diet after one month. The typical hospital stay is 2-3 days, and many patients can return to work after about a week. If the surgery is done open instead of laparoscopically, patients may need to take a month off work. Heavy lifting is typically restricted for six weeks or more. The Heller myotomy is a long-term treatment, and many patients do not require any further treatment. However, some will eventually need pneumatic dilation, repeat myotomy (usually performed as an open procedure the second time around), or esophagectomy. It is important to monitor changes in the shape and function of the esophagus with an annual timed barium swallow. Regular endoscopy may also be useful to monitor changes in the tissue of the esophagus, since reflux may damage the esophagus over time, potentially leading to a premalignant condition known as Barrett's esophagus and increasing the risk of cancer. Though this surgery does not correct the underlying cause and does not completely eliminate achalasia symptoms, the vast majority of patients find that the surgery greatly improves their ability to eat and drink. It is considered the definitive treatment for achalasia.

Hymen # Overview The hymen (also called maidenhead) is a fold of mucous membrane which surrounds or partially covers the external vaginal opening. Its name comes from the ancient greek for "hymenaeus," which means "vaginal-flap." It was also the name for the Greek god of marriage, later also the Greek god of membranes; "Hymenaios." A slang term is "cherry", as in "popping one's cherry" (losing one's virginity). It forms part of the vulva, or external genitalia. The most common formation of the hymen is crescentic or crescent-shaped, although several other formations are possible. After a woman gives birth she may be left with remnants of the hymen called carunculae myrtiformes or the hymen may be completely absent. The hymen has no known anatomical function. In societies which value chastity, the greatest significance of the hymen is a traditional belief that an intact hymen indicates a state of intact virginity. However, it is not possible to confirm that a woman or post-pubescent girl is not a virgin by examining the hymen. A physician routinely checks the appearance of the hymen of baby girls at birth, and again during all future pelvic examinations. In cases of suspected rape or sexual abuse, a detailed examination of the hymen may be carried out; however, the condition of the hymen alone is often inconclusive or open to misinterpretation, especially if the patient has reached puberty. # Types There are several different formations of the hymen, some more common than others. In about 1 in 2000 females, the hymen fails to develop any opening at all: this is called an imperforate hymen and if it does not spontaneously resolve itself before puberty a physician will need to make a hole in the hymen to allow menstrual fluids to escape. A hymenotomy may also be required if the hymen is particularly thick or inelastic as it may interfere with sexual intercourse. The shape of the hymen is easiest to observe in girls past infancy but before they reach puberty: at this time their hymen is thin and less likely to be redundant, that is to protrude or fold over on itself. When describing the shape of a hymen, a clock face is used. The 12 o'clock position is below the urethra, and 6 o'clock is towards the anus, which is based on the patient lying on her back. ## Most common forms of the hymen - crescent-shaped, crescentic, or posterior rim: no hymenal tissue at the 12 o'clock position; narrow band of tissue starts at 1 or 2 o'clock going clockwise, is at its widest around 6 o'clock, and tapers off at 10 or 11 o'clock - annular, or circumferential: the hymen forms a ring around the vaginal opening; especially common in newborns - redundant; sometimes sleeve-like: folds in on itself, which sometimes causes it to protrude; most common in infancy and at/following puberty due to estrogen levels; can be combined with other type such as "annular and redundant" ## Less common forms - Fimbriated or denticular: an irregular edge to the hymenal orifice; more likely at an age when estrogen is present - Septate: the hymen has one or more bands extending across the opening - Cribriform, or microperforate: the hymen stretches completely across the vaginal opening, but is perforated with several holes - Labial, or vertical: hymen has an opening from the 12 to the 6 o'clock positions and can look similar to a third set of vulvar lips - Imperforate: hymen completely covers vaginal orifice; will require minor surgery if it has not corrected itself by puberty to allow menstrual fluids to escape Imperforated hymen must be differentiated from other diseases that cause latency in secondary sexual characteristics development (amenorrhea), such as constitutional delay of puberty, hypopituitarism, delayed puberty, and chromosomal abnormalities. Chromosomal abnormalities are Turner's syndrome, and Noonan's syndrome. - Imperforated hymen must be differentiated from other diseases that cause latency in secondary sexual characteristics development (amenorrhea), such as constitutional delay of puberty, hypopituitarism, delayed puberty, and chromosomal abnormalities. Chromosomal abnormalities are Turner's syndrome, and Noonan's syndrome. The hymen is torn or stretched by penetrative sex, and more so when a woman gives birth vaginally. - parous introitus refers to the vaginal opening which has had a baby pass through it and consequently has nothing left of its hymen but a fleshy irregular outline decorating its perimeter; these tags are called carunculae mytriformes # Development of the hymen During the early stages of fetal development there is no opening into the vagina at all. The thin layer of tissue that covers the vagina at this time usually divides to a certain extent prior to birth, forming the hymen. That layer was the Müllerian eminence before, and thus, the hymen is a remnant of that structure. In newborn babies, who are still under the influence of the mother's hormones, the hymen is thick, pale pink, and redundant (folds in on itself and may protrude). For the first two to four years of life, the infant produces hormones which continue this effect. By the time a girl reaches school-age, this hormonal influence has stopped and the hymen becomes thin, smooth, delicate and almost translucent. It is also very sensitive to touch; a physician who needed to swab the area would avoid the hymen and swab the outer vulval vestibule instead. From puberty onwards the appearance of the hymen is affected once more by estrogen. It thickens and becomes pale pink, the opening is often fibriated or erratically shaped, and redundant: the hymen often appears rolled or sleeve-like. There is a surgical procedure that can repair the hymen so that it is intact. The procedure, known as hymenoplasty, has become a popular procedure for some females. # What might damage the hymen? The hymen may be damaged by playing sports, using tampons, pelvic examinations or even straddle injuries. Once a girl reaches puberty, the hymen tends to become quite elastic. It is not possible to determine whether a woman uses tampons or not by examining her hymen. Sexual intercourse is one of the most common ways to damage the hymen, although in one survey only 43% of women reported bleeding the first time they had sex; which means that in the other 57% of women the hymen likely stretched enough that it didn't tear. It is rare to damage the hymen through accidental injury, such as falling on the top tube of a bicycle. Although such an accident may cause bleeding, this is usually due to damage to surrounding tissues such as the labia. It is unlikely that an accident would damage the hymen without injuring any other part of the vulva. Therefore, damage to the hymen alone, described as an accident, would be seen as a strong indicator of sexual assault. # Debunking myths - The condition of the hymen is not a reliable indicator of whether a woman past puberty has actually engaged in sexual intercourse. - There is no such thing as "congenital absence of the hymen", i.e. it is a myth that girls are born without a hymen. However, a hymen can vary in size, and, as described above, be very hard to find, even if the person never had sex before. - The hymen is not inside the vagina. It is part of the external genitalia. As early as the late sixteenth century, Ambroise Paré and Andreas Laurentius asserted to have never seen the hymen and that it was "a primitive myth, unworthy of a civilized nation like France." In the sixteenth and seventeenth centuries, medical researchers have used the presence of the hymen, or lack thereof, as founding evidence of physical diseases such as "womb-fury". If not cured, womb-fury would, according to these early doctors, result in death. The cure, naturally enough, was marriage, since a woman could then go about having sexual intercourse on a "normal" schedule that would stop womb-fury from killing her. # Revisionist perspectives In late 2005, Monica Christiansson, former maternity ward nurse and Carola Eriksson, a PhD student at Umeå University announced that according to studies of medical literature and practical experience, the hymen should be considered a social and cultural myth, based on deeply rooted stereotypes of womens' roles in sexual relations with men. Christiansson and Eriksson support their claims by pointing out that there are no accurate medical descriptions of what a hymen actually consists of. Statistics presented by the two state that fewer than 30% of women who have gone through puberty and have consensual intercourse bleed the first time. Christiansson has expressed an opinion that the use of the term "hymen" should be discontinued and that it should be considered an integral part of the vaginal opening. It is argued that since the hymen has been culturally constructed to be the sign of virginity, its existence plays into a political discourse that circulates around the body. By examining women's bodies for the existence of the hymen, researchers have used it to determine whether or not women are "virtuous." Sherry B. Ortner, professor at the University of Chicago, explains how "the hymen itself emerges physiologically with the development of sexual purity codes" as an element of patriarchy. In some cultures it was customary to examine a woman for her hymen before her marriage to see if she was truly fit to be married. If she was found with a broken hymen, or to have no hymen at all, often the male would not be obligated to marry her. Additionally, the hymen has been used to consistently create the image of women as physically bound to their sexuality, insofar as there's a specific membrane that needs "breaking" in order to have sex and enter into full womanhood, being sexually dependent on their men.

Quinine Sulfate clinical pharmacology # Clinical Pharmacology ## Pharmacodynamics QTc interval prolongation was studied in a double-blind, multiple dose, placebo- and positive-controlled crossover study in young (N=13, 20 to 39 years) and elderly (N=13, 65 to 78 years) subjects. After 7 days of dosing with QUALAQUIN 648 mg three times daily, the maximum mean (95% upper confidence bound) differences in QTcI from placebo after baseline correction was 27.7 (32.2) ms. Prolongation of the PR and QRS interval was also noted in subjects receiving QUALAQUIN. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 14.5 (18.0) ms. The maximum mean (95% upper confidence bound) difference in QRS from placebo after baseline-correction was 11.5 (13.3) ms. . ## Pharmacokinetics ### Absorption The oral bioavailability of quinine is 76 to 88% in healthy adults. Quinine exposure is higher in patients with malaria than in healthy subjects. After a single oral dose of quinine sulfate, the mean quinine Tmax was longer, and mean AUC and Cmax were higher in patients with uncomplicated P. falciparum malaria than in healthy subjects, as shown in Table 1 below. QUALAQUIN capsules may be administered without regard to meals. When a single oral 324 mg capsule of QUALAQUIN was administered to healthy subjects (N=26) with a standardized high-fat breakfast, the mean Tmax of quinine was prolonged to about 4.0 hours, but the mean Cmax and AUC0-24h were similar to those achieved when QUALAQUIN capsule was given under fasted conditions . ### Distribution In patients with malaria, the volume of distribution (Vd/F) decreases in proportion to the severity of the infection. In published studies with healthy subjects who received a single oral 600 mg dose of quinine sulfate, the mean Vd/F ranged from 2.5 to 7.1 L/kg. Quinine is moderately protein-bound in blood in healthy subjects, ranging from 69 to 92%. During active malarial infection, protein binding of quinine is increased to 78 to 95%, corresponding to the increase in α1-acid glycoprotein that occurs with malaria infection. Intra-erythrocytic levels of quinine are approximately 30 to 50% of the plasma concentration. Quinine penetrates relatively poorly into the cerebrospinal fluid (CSF) in patients with cerebral malaria, with CSF concentration approximately 2 to 7% of plasma concentration. In one study, quinine concentrations in placental cord blood and breast milk were approximately 32% and 31%, respectively, of quinine concentrations in maternal plasma. The estimated total dose of quinine secreted into breast milk was less than 2 to 3 mg per day . ### Metabolism Quinine is metabolized almost exclusively via hepatic oxidative cytochrome P450 (CYP) pathways, resulting in four primary metabolites, 3-hydroxyquinine, 2´-quinone, O-desmethylquinine, and 10,11-dihydroxydihydroquinine. Six secondary metabolites result from further biotransformation of the primary metabolites. The major metabolite, 3-hydroxyquinine, is less active than the parent drug. In vitro studies using human liver microsomes and recombinant P450 enzymes have shown that quinine is metabolized mainly by CYP3A4. Depending on the in vitro experimental conditions, other enzymes, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 were shown to have some role in the metabolism of quinine. ### Elimination/Excretion Quinine is eliminated primarily via hepatic biotransformation. Approximately 20% of quinine is excreted unchanged in urine. Because quinine is reabsorbed when the urine is alkaline, renal excretion of the drug is twice as rapid when the urine is acidic than when it is alkaline. In various published studies, healthy subjects who received a single oral 600 mg dose of quinine sulfate exhibited a mean plasma clearance ranging from 0.08 to 0.47 L/h/kg (median value: 0.17 L/h/kg) with a mean plasma elimination half-life of 9.7 to 12.5 hours. In 15 patients with uncomplicated malaria who received a 10 mg/kg oral dose of quinine sulfate, the mean total clearance of quinine was slower (approximately 0.09 L/h/kg) during the acute phase of the infection, and faster (approximately 0.16 L/h/kg) during the recovery or convalescent phase. Extracorporeal Elimination: Administration of multiple-dose activated charcoal (50 grams administered 4 hours after quinine dosing followed by 3 further doses over the next 12 hours) decreased the mean quinine elimination half-life from 8.2 to 4.6 hours, and increased the mean quinine clearance by 56% (from 11.8 L/h to 18.4 L/h) in 7 healthy adult subjects who received a single oral 600 mg dose of quinine sulfate. Likewise, in 5 symptomatic patients with acute quinine poisoning who received multiple-dose activated charcoal (50 grams every 4 hours), the mean quinine elimination half-life was shortened to 8.1 hours in comparison to a half-life of approximately 26 hours in patients who did not receive activated charcoal . In 6 patients with quinine poisoning, forced acid diuresis did not change the half-life of quinine elimination (25.1 ± 4.6 hours vs. 26.5 ± 5.8 hours), or the amount of unchanged quinine recovered in the urine, in comparison to 8 patients not treated in this manner . ### Specific Populations The pharmacokinetics of quinine in children (1.5 to 12 years old) with uncomplicated P. falciparum malaria appear to be similar to that seen in adults with uncomplicated malaria. Furthermore, as seen in adults, the mean total clearance and the volume of distribution of quinine were reduced in pediatric patients with malaria as compared to the healthy pediatric controls. Table 2 below provides a comparison of the mean ± SD pharmacokinetic parameters of quinine in pediatric patients vs. healthy pediatric controls. Following a single oral dose of 600 mg quinine sulfate, the mean AUC was about 38% higher in 8 healthy elderly subjects (65 to 78 years old) than in 12 younger subjects (20 to 35 years old). The mean Tmax and Cmax were similar in elderly and younger subjects after a single oral dose of quinine sulfate 600 mg. The mean oral clearance of quinine was significantly decreased, and the mean elimination half-life was significantly increased in elderly subjects compared with younger subjects (0.06 vs. 0.08 L/h/kg, and 18.4 hours vs. 10.5 hours, respectively). Although there was no significant difference in the renal clearance of quinine between the two age groups, elderly subjects excreted a larger proportion of the dose in urine as unchanged drug than younger subjects (16.6% vs. 11.2%). After a single 648 mg dose or at steady state, following quinine sulfate 648 mg given three times daily for 7 days, no difference in the rate and extent of absorption or clearance of quinine was seen between 13 elderly subjects (65 to 78 years old) and 14 young subjects (20 to 39 years old). The mean elimination half-life was 20% longer in the elderly subjects (24.0 hours) than in younger subjects (20.0 hours). The steady state Cmax (±SD) and AUC0-8 (±SD) for healthy volunteers are 6.8 ± 1.24 mcg/mL and 48.8 ± 9.15 mcg*h/mL, respectively, following 7 days of oral quinine sulfate 648 mg three times daily. The steady state pharmacokinetic parameters in healthy elderly subjects were similar to the pharmacokinetic parameters in healthy young subjects. Following a single oral 600 mg dose of quinine sulfate in otherwise healthy subjects with severe chronic renal failure not receiving any form of dialysis (mean serum creatinine = 9.6 mg/dL), the median AUC was higher by 195% and the median Cmax was higher by 79% than in subjects with normal renal function (mean serum creatinine = 1 mg/dL). The mean plasma half-life in subjects with severe chronic renal impairment was prolonged to 26 hours compared to 9.7 hours in the healthy controls. Computer assisted modeling and simulation indicates that in patients with malaria and severe chronic renal failure, a dosage regimen consisting of one loading dose of 648 mg QUALAQUIN followed 12 hours later by a maintenance dosing regimen of 324 mg every 12 hours will provide adequate systemic exposure to quinine . The effects of mild and moderate renal impairment on the pharmacokinetics and safety of quinine sulfate are not known. Negligible to minimal amounts of circulating quinine in the blood are removed by hemodialysis or hemofiltration. In subjects with chronic renal failure (CRF) on hemodialysis, only about 6.5% of quinine is removed in 1 hour. Plasma quinine concentrations do not change during or shortly after hemofiltration in subjects with CRF . In otherwise healthy subjects with mild hepatic impairment (Child-Pugh A; N=10), who received a single 500 mg dose of quinine sulfate, there was no significant difference in quinine pharmacokinetic parameters or exposure to the primary metabolite, 3-hydroxyquinine as compared to healthy controls (N=10). In otherwise healthy subjects with moderate hepatic impairment (Child-Pugh B; N=9) who received a single oral 600 mg dose of quinine sulfate, the mean AUC increased by 55% without a significant change in mean Cmax, as compared to healthy volunteer controls (N=6). In subjects with hepatitis, the absorption of quinine was prolonged, the elimination half-life was increased, the apparent volume of distribution was higher, but there was no significant difference in weight-adjusted clearance. Therefore, in patients with mild to moderate hepatic impairment, dosage adjustment is not needed, but patients should be monitored closely for adverse effects of quinine . In subjects with severe hepatic impairment (Child-Pugh C; N=10), quinine oral clearance (CL/F) was reduced as was formation of the primary 3-hydroxyquinine metabolite. Volume of distribution (Vd/F) was higher and the plasma elimination half-life was increased. Therefore, quinine is not indicated in this population and alternate therapy should be administered

PCA3 Prostate cancer antigen 3 (PCA3, also referred to as DD3) is a gene that expresses a non-coding RNA. PCA3 is only expressed in human prostate tissue, and the gene is highly overexpressed in prostate cancer. Because of its restricted expression profile, the PCA3 RNA is useful as a tumor marker. # Use as biomarker The most frequently used biomarker for prostate cancer today is the serum level of prostate-specific antigen (PSA), or derived measurements. However, since PSA is prostate-specific but not cancer-specific, it is an imperfect biomarker. For example, PSA can increase in older men with benign prostatic hyperplasia. Several new biomarkers are being investigated to improve the diagnosis of prostate cancer. Some of these can be measured in urine samples, and it is possible that a combination of several urinary biomarkers will replace PSA in the future. Compared to serum PSA, PCA3 has a lower sensitivity but a higher specificity and a better positive and negative predictive value. It is independent of prostate volume, whereas PSA is not. It should be measured in the first portion of urine after prostate massage with digital rectal examination. PCA3 has been shown to be useful to predict the presence of malignancy in men undergoing repeat prostate biopsy. This means that it could be useful clinically for a patient for whom digital rectal examination and PSA suggest possible prostate cancer, but the first prostate biopsy returns a normal result. This occurs in approximately 60% of cases, and on repeat testing, 20-40% have an abnormal biopsy result. Other uses that are being studied for PCA3 include its correlation with adverse tumor features such as tumor volume, grading (Gleason score) or extracapsular extension. These studies have so far produced conflicting results. # Society and culture A commercial kit called the Progensa PCA3 test is marketed by the Californian company Gen-Probe. Gen-Probe acquired rights to the PCA3 test from Diagnocure in 2003. In April 2012, Hologic bought Gen-Probe for $3.75 billion by cash. # Discovery PCA3 was discovered to be highly expressed by prostate cancer cells in 1999.

Bernard Lown # Overview Bernard Lown, M.D. was the original developer of the defibrillator and is an internationally known peace activist. Born in Lithuania, he emigrated at age 13 with his parents to the US, initially to Maine shortly before the outbreak of World War II, and subsequently studied to become a specialist in cardiology. # Development of the defibrillator Up until the late 1950's, fibrillation of the heart could be treated only by drug therapy. In 1956 American cardiologist Paul Zoll published a paper describing resuscitation of open-heart surgery patients by means of a 110 volt alternating current electric shock (derived from a wall socket) and conducted to the sides of the exposed heart by metal plate "paddles". While being an advance in emergency resuscitation, the technique was later to be shown to be both damaging to the heart muscle and of unpredictable effectiveness in reverting ventricular fibrillation. In 1959, Lown, aware of the Zoll paper and of the complications resulting from the alternating current method, commenced animal research in an endeavour to define a less traumatic and more effective form of electric shock. This work resulted in what became known as the "Lown waveform"; a single heavily damped sinusoidal waveform with a half cycle time of approximately 5 milliseconds. The waveform was produced by charging a bank of capacitors to about 1000 volts, then discharging the capacitors through an inductor to deliver the waveform to the heart. Following the research findings, Lown contacted engineer Barouh Berkovits of the American Optical Company, who produced a clinical prototype defibrillator (often referred to as a "cardioverter") which became the basis for further technological evolution. The original machine, weighing some 60 lb (27 kg), delivered the Lown waveform at energy levels up to 100 joules for exposed heart application, and 200–400 joules for transthoracic application. # Peace activist In 1960 he was one of the founders of Physicians for Social Responsibility and later the co-founder of International Physicians for the Prevention of Nuclear War. He also founded two organisations, SATELLIFE and ProCOR, which provide health information and assistance to developing countries. International Physicians for the Prevention of Nuclear War was awarded the 1985 Nobel Peace Prize. Bernard Lown is currently Professor of Cardiology Emeritus at the Harvard School of Public Health. He and his wife Louise have three children.

Posaconazole drug interactions # Drug Interactions Posaconazole is primarily metabolized via UDP glucuronidation and is a substrate of p-glycoprotein efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Coadministration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections. Posaconazole is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole . ## Immunosuppressants Metabolized by CYP3A4 Sirolimus: Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity. Therefore, posaconazole is contraindicated with sirolimus . Tacrolimus: Posaconazole has been shown to significantly increase the Cmax and AUC of tacrolimus. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly. Cyclosporine: Posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly . ## CYP3A4 Substrates Concomitant administration of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes. Therefore, posaconazole is contraindicated with these drugs . ## HMG-CoA Reductase Inhibitors (Statins) Primarily Metabolized Through CYP3A4 Concomitant administration of posaconazole with simvastatin increases the simvastatin plasma concentrations by approximately 10-fold. Therefore, posaconazole is contraindicated with HMG-CoA reductase inhibitors primarily metabolized through CYP3A4 . ## Ergot Alkaloids Most of the ergot alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Therefore, posaconazole is contraindicated with ergot alkaloids . ## Benzodiazepines Metabolized by CYP3A4 Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant use of posaconazole and other benzodiazepines metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by CYP3A4 and benzodiazepine receptor antagonists must be available to reverse these effects . ## Anti-HIV Drugs Efavirenz: Efavirenz induces UDP-glucuronidase and significantly decreases posaconazole plasma concentrations . It is recommended to avoid concomitant use of efavirenz with posaconazole unless the benefit outweighs the risks. Ritonavir and Atazanavir: Ritonavir and atazanavir are metabolized by CYP3A4 and posaconazole increases plasma concentrations of these drugs . Frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with posaconazole. Fosamprenavir: Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended . ## Rifabutin Rifabutin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Rifabutin is also metabolized by CYP3A4. Therefore, coadministration of rifabutin with posaconazole increases rifabutin plasma concentrations . Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections as well as frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) are recommended. ## Phenytoin Phenytoin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Phenytoin is also metabolized by CYP3A4. Therefore, coadministration of phenytoin with posaconazole increases phenytoin plasma concentrations . Concomitant use of posaconazole and phenytoin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations should be performed while coadministered with posaconazole and dose reduction of phenytoin should beconsidered. ## Gastric Acid Suppressors/Neutralizers Posaconazole Delayed-Release Tablet: No clinically relevant effects on the pharmacokinetics of posaconazole were observed when posaconazole delayed-release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors . No dosage adjustment of posaconazole delayed-release tablets is required when posaconazole delayed-release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors. Posaconazole Oral Suspension: Cimetidine (an H2-receptor antagonist) and esomeprazole (a proton pump inhibitor) when given with posaconazole oral suspension results in decreased posaconazole plasma concentrations . It is recommended to avoid concomitant use of cimetidine and esomeprazole with posaconazole oral suspension unless the benefit outweighs the risks. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended. No clinically relevant effects were observed when posaconazole oral suspension is concomitantly used with antacids and H2-receptor antagonists other than cimetidine. No dosage adjustment of posaconazole oral suspension is required when posaconazole oral suspension is concomitantly used with antacids and H2-receptor antagonists other than cimetidine. ## Vinca Alkaloids Most of the vinca alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of vinca alkaloids (e.g., vincristine and vinblastine) which may lead to neurotoxicity. Therefore, it is recommended that dose adjustment of the vinca alkaloid be considered. ## Calcium Channel Blockers Metabolized by CYP3A4 Posaconazole may increase the plasma concentrations of calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, diltiazem, nifedipine, nicardipine, felodipine). Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during coadministration. Dose reduction of calcium channel blockers may be needed. ## Digoxin Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and posaconazole. Therefore, monitoring of digoxin plasma concentrations is recommended during coadministration. ## Gastrointestinal Motility Agents Posaconazole Delayed-Release Tablet: Concomitant administration of metoclopramide with posaconazole delayed-release tablets did not affect the pharmacokinetics of posaconazole. No dosage adjustment of posaconazole delayed-release tablets is required when given concomitantly with metoclopramide. Posaconazole Oral Suspension: Metoclopramide, when given with posaconazole oral suspension, decreases posaconazole plasma concentrations . If metoclopramide is concomitantly administered with posaconazole oral suspension, it is recommended to closely monitor for breakthrough fungal infections. Loperamide does not affect posaconazole plasma concentrations . No dosage adjustment of posaconazole is required when loperamide and posaconazole are used concomitantly. ## Glipizide Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when posaconazole and glipizide are concomitantly used.

Aortic stenosis overview # Overview The aortic valve ensures that the blood moves forward from the left ventricle into the aorta and that it does not leak backwards during diastole. When functioning appropriately, the aortic valve does not impede the flow of blood between the left ventricle and the aorta and it does not leak. Under some circumstances, the aortic valve becomes narrower than normal impeding the flow of blood. This is known as aortic valve stenosis, or aortic stenosis, often abbreviated as AS. # Classification Aortic stenosis can be classified broadly into two main categories: acquired and congenital. Further classification can be applied based on the origin of the stenosis such as acquired rheumatic, congenital bicuspid, congenital subaortic, congenital subvalvular, and congenital supravalvular aortic stenosis. # Pathophysiology Aortic stenosis is the progressive narrowing of the aortic valve. Calcific aortic stenosis, in particular, is an active atherosclerotic pathology where inflammation, fibrosis and calcification are involved in the progressive narrowing of the effective aortic valve area in the absence of any commissural fusion. In contrast, rheumatic aortic stenosis is due to fusion of the commissures with valvular scarring and calcification. Aortic stenosis causes an impedance to the antegrade blood flow not only at the level of the aortic valve itself, but also at the subvalvular (below the aortic valve) or supravalvular (above the aortic valve) levels. As a result, chronic pressure overload develops in the left ventricle. The left ventricle undergoes hypertrophy as an initial adaptive mechanism to overcome the increased afterload. This compensatory mechanism ends up being maladpative by causing apoptosis of the hypertrophied myocytes and subsequent heart failure. Hence, aortic stenosis is a progressive valvular disease which progression depends mainly on the degree of the narrowing of the aortic valve as well as on the maladaptive ventricular wall response. # Causes The frequency of causes of aortic stenosis varies with the age of the patient. Bicuspid valve is the most common cause of aortic stenosis in people below 50 years of age whereas calcified aortic valve is more common in older patients. # Differentiating Aortic Stenosis from other Disorders Aortic stenosis must be differentiated from other cardiac or pulmonary causes of dyspnea, weakness, and dizziness. Furthermore, if there is left ventricular outflow tract obstruction, it is critical to identify whether the obstruction is subvalvular, valvular or supravalvular or due to hypertrophic cardiomyopathy (HOCM). # Epidemiology and Demographics Aortic stenosis primarily affects older adults and the majority of cases are due to calcific degeneration. Aortic stenosis tends to affect approximately 2% of patients over the age of 65, 3% of patients over the age of 75, and 4% of patients over the age 85. # Risk Factors The most common risk factor for the subsequent development of aortic stenosis is congenital bicuspid aortic valve. Rheumatic fever is another risk factor for the subsequent development of aortic stenosis (rheumatic heart disease). Risk factors that may speed up the progression of degenerative calcific aortic stenosis include: hypertension, diabetes mellitus, hyperlipoproteinemia, uremia and smoking. # Natural History, Complications and Prognosis Left untreated, aortic valve stenosis can lead to angina, syncope, congestive heart failure, atrial fibrillation, endocarditis, and sudden cardiac death. Surgical treatment of aortic stenosis also carries risks and potential complications that include vascular complications and mitral valve injury. # Diagnosis ### History and Symptoms The main symptoms of aortic stenosis include angina, syncope and congestive heart failure. Left untreated, the average survival is 5 years after the onset of angina, 3 years after the onset of syncope, and 1 year after the onset of congestive heart failure. Other symptoms include dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea. ### Physical Examination Aortic stenosis is most often diagnosed when it is asymptomatic and can sometimes be detected during routine examination of the heart and circulatory system. The major signs include pulsus parvus et tardus (a slow-rising, small volume carotid pulse), a lag time between apical and carotid impulses, and a distinct systolic ejection murmur. ### Electrocardiogram The electrocardiogram in the patient with moderate to severe aortic stenosis may reveal left ventricular hypertrophy and heart block. ### Cardiac Stress Test Exercise testing should not be performed in symptomatic patients with AS but can be used to elicit exercise-induced symptoms and abnormal blood pressure responses in asymptomatic patients. ### Chest X-ray Chest X-ray may be used as a diagnostic tool in the evaluation of aortic stenosis. Findings associated with aortic stenosis include left ventricular hypertrophy and calcification of the aortic valve. ### CT Scan Computed tomography can be helpful as a diagnostic tool in conditions where the echocardiographic findings are inconclusive. ### MRI Magnetic resonance imaging is rarely used in the diagnosis of aortic stenosis, except in rare cases where the echocardiographic findings are inconclusive. There is a signal void where the high velocity jet exits the aortic valve. ### Echocardiography Echocardiography is the best non-invasive test to evaluate the aortic valve anatomy and function. It is indicated in the case of presence of symptoms suggestive of valvular problems or in the case of detection of a systolic murmur with a grade greater than 3/6. Doppler echocardiography allows the measurement of the maximum jet velocity and can be used to estimate the effective orifice area of the aortic valve as well as the gradient across the aortic valve using the modified Bernoulli equation (gradient = 4 x velocity2). The flow must be constant, so as the velocity increases, the valve area decreases proportionally. Attention to technical details is important as they may lead to underestimation of the severity of the aortic stenosis. Echocardiography can also be used to assess the severity of left ventricular hypertrophy. ### Cardiac Catheterization Left and right heart catheterization as well as angiography may be useful in the assessment of the patient prior to aortic valve replacement surgery. In addition, asymptomatic patients with aortic stenosis should undergo cardiac catherization when echocardiographic findings are inconsistent with the clinical findings. ### Aortic Valve Area The aortic valve area is the size of the orifice for blood to flow from the left ventricle to the aorta. The aortic valve area is reduced in aortic stenosis, and the aortic valve area is the metric that is used to gauge the need for aortic valve replacement surgery. The pressure gradient across a narrowed aortic valve cannot be used to gauge the need for valve replacement as the gradient may be low in patients with impaired left ventricular function. ### Aortic Valve Area Calculation The calculation of the aortic valve area is an indirect method used to determine the area of the aortic valve. The calculated aortic valve orifice area is currently one of the measures for evaluating the severity of aortic stenosis. An aortic valve having an area less than 0.8 cm² is considered to be severe aortic stenosis. There are many ways to calculate the aortic valve area. The most commonly used methods involve measurements taken during echocardiography. For interpretation of these values, the aortic valve area is generally divided by the body surface area. # Treatment ## General Approach Once a patient becomes symptomatic with aortic stenosis, aortic valve replacement should be performed as long as the patient can tolerate surgery and has no co-morbidities. If severe left ventricular dysfunction is present in the setting of aortic stenosis, it is of utmost importance to differentiate between true severe aortic stenosis and pseudo-severe aortic stenosis as these two entities have different pathophysiologies and different outcomes after aortic valve replacement. Medical therapy reduces symptoms but does not prolong life. If a patient has extensive co-morbidities, transcatheter aortic valve implantation can be considered. Aortic valvuloplasty can be considered in those patients who are too sick for surgery or transcatheter aortic valve implantation. ## Medical Therapy While medical therapy may improve the symptoms of patients with aortic stenosis, medical therapy does not prolong life expectancy. Aortic valve replacement remains the definitive treatment for symptomatic aortic stenosis and it improves both the symptoms and life expectancy of the patients. When pharmacological therapies are used, extreme caution must be taken in the administration of vasodilators as an excess in vasodilation may lead to hypotension, a reduction in perfusion pressure to the heart, a further decline in cardiac output and further hypotension. This vicious circle can be fatal and must be avoided at all costs. ## Surgery Surgical intervention may be a necessary component of treatment for symptomatic severe aortic stenosis. Aortic valve replacement is the mainstay of treatment of symptomatic aortic stenosis, as it improves both the symptoms and life expectancy in aortic stenosis patients, in contrast to medical therapy alone which may improve the symptoms without prolonging life expectancy. ## Percutaneous Aortic Balloon Valvotomy (PABV) or Aortic Valvuloplasty Surgical aortic valve replacement is the mainstay of the treatment of aortic stenosis as it improves both symptoms and life expectancy. However, some patients may not be surgical candidates due to coexisting comorbidities. Hence, minimally invasive treatment such as percutaneous aortic balloon valvotomy (PABV) maybe an alternative to surgery as a palliative strategy. PABV is a procedure during which one or more balloons are placed across a stenotic valve and then inflated in order to cause a decrease the severity of aortic stenosis. This is to be distinguished from transcatheter aortic valve implantation (TAVI) which is a different method that involves replacement of the valve percutaneously. ## Transcatheter Aortic Valve Implantation Until recently, aortic valve replacement (AVR) was the only effective treatment for severe symptomatic aortic stenosis. However, over the past decade percutaneous treatment of aortic valve disease with the implantation of a stent-based valve prosthesis has been introduced as a new treatment in patients considered inoperable because of severe co-morbidities. In Transcatheter Aortic Valve Implantation (TAVI) also known as Percutaneous Aortic Valve Replacement (PAVR), a synthetic valve is advanced to the heart through a small hole made in the groin. This procedure is similar in its mechanism to the insertion of a stent, or performing balloon angioplasty albeit with much larger equipment. Traditional aortic valve replacement is an invasive surgical procedure, with considerable mortality and morbidity, especially in more fragile patients. In the newly developed TAVI procedure, the dysfunctional aortic valve is replaced percutaneously, which obviates the need for open heart surgery. ## Follow Up Follow up is recommended for all patients with operated and unoperated aortic stenosis. Asymptomatic patients with aortic stenosis should undergo follow up since aortic stenosis is an ongoing disease that progresses with time. In fact, asymptomatic patients should undergo follow up every 1 year, 3 years and 5 years in case of severe, moderate and mild aortic stenosis respectively. ## Prevention Aortic stenosis associated with rheumatic heart disease can be minimized with antibiotic therapy in patients with documented streptococcal pharyngitis (strep throat).Bicuspid aortic valve disease is a congenital variant and cannot be prevented. Calcific degeneration of the valve can potentially be minimized by rosouvistatin and other measures targeting prevention of atherosclerosis. ## Precautions and Prophylaxis People with aortic stenosis of any etiology are at risk for the development of infection of their stenosed valve, i.e. infective endocarditis and antibiotic prophylaxis should be considered. Patients with severe aortic stenosis should avoid strenuous exercise and any exercise that greatly increases afterload such as weight lifting.

Organophosphorus # Overview Organophosphorus compounds are chemical compounds containing carbon-phosphorus bonds. Organophosphorus chemistry is the corresponding science exploring the properties and reactivity of organophosphorus compounds. Phosphorus shares group 15 in the periodic table with nitrogen and phosphorus compounds and nitrogen compounds have much in common. Phosphorus can adopt oxidation states −3, −1, 1, 3 and 5. In chemical literature very often compounds with +3 or −3 oxidation state are grouped together as having a (III) oxidation state regardless of sign. In an official and more descriptive nomenclature phosphorus compounds are identified by their coordination number δ and their valency λ. In this system a phosphine is a δ3λ3 compound. # Phosphanes & phosphines The parent compound of the phosphanes is PH3, called phosphine in the US and UK and phosphane elsewhere. Replacement of one or more protons by an organic residue, gives PH3-xRx, an organophosphine or organophosphane, again depending on the country. The phosphorus atom in phosphanes/phosphines has a formal oxidation state −3 (δ3λ3) and are the phosphorus analogues of simple amines. An often used organic phosphine is triphenylphosphine. Like amines, phosphines have a trigonal pyramidal molecular geometry although with larger angles. The C-P-C bond angle is 98.6° for trimethylphosphine increasing to 109.7° when the methyl groups are replaced by tert-butyl groups. Commonly the size of these ligands are described by the parameter called cone angle. The barrier to inversion is also much higher than in amines for a process like nitrogen inversion to occur and therefore phosphines with three different substituents can display optical isomerism. The basicity of phospines is less than that of corresponding amines, for instance phosphonium ion itself has a pKa of -14 compared to 9.21 for ammonium ion; trimethylphosphonium has a pKa of 8.65 compared to that of 9.76 of trimethylamine; and triphenylphosphonium (pKa 11.2) is less basic than triphenylammonium (pKa 19). Amines and phosphines both have a lone pair of electrons but with a difference. Whereas the lone pair in an amine shares its electrons at every opportunity for delocalization for instance in pyridine, the phosphorus atom in a similar configuration will not. For this reason, the phosphorus equivalent of pyrrole called phosphole is not at all aromatic. The reactivity of phosphines match that of amines with regard to nucleophilicity in the formation of Phosphonium salts with the general structure PR4+X−. This property is used in the Appel reaction converting alcohols to alkyl halides. A difference in reactivity with amines is the ease of oxidation of phosphines to phosphine oxides. ## Synthesis Synthetic produces for phosphines are: - Nucleophilic displacement of phosphorous halides with organometallic reagents such as Grignard reagents. - Nucleophilic displacement of metal phosphides, generated by reaction of potassium metal with phosphine as in sodium amide with alkyl halides. - Nucleophilic addition of phosphine with alkenes in presence of a strong base (often KOH in DMSO), Markovnikov's rules apply. Phosphine can be prepared in situ from red phosphorus and potassium hydroxide. Primary (RPH2) and secondary phospines (RRPH) do not require a base with electron-deficient alkenes such as acrylonitriles. - Radical addition of phosphines to alkenes with AIBN or organic peroxides to give anti-Markovnikov adducts. - Nucleophilic addition of phosphine and phosphines to alkynes in presence of base. Secondary phosphines react with electron-deficient alkynes such as phenylcyanoacetylene without base. - Organic reduction of phosphine oxides for instance with chlorosilane. ## Reactions The main reaction types of phosphines are: - as nucleophiles for instance with alkyl halides to phosphonium salts. Phospines are key nucleophilic catalysts in the dimerization of enones in the Rauhut-Currier reaction. - as reducing agents: - Multidentate phosphines such as BINAP are important ligands in organometallic chemistry. ## Phosphanes Primary phosphanes are under-used in chemistry due to their general lack of stability towards oxygen. One study reports on several novel air-stable aromatic primary phosphanes prepared by organic reduction of the corresponding phosphonate: The stability is attributed to conjugation between the aromatic ring and the phosphorus lone pair. # Phosphine oxides Phosphine oxides (designation δ3λ3) have the general structure R3P=O with formal oxidation state −1. Phosphines form hydrogen bonds and many phosphines are therefore soluble in water. The P=O bond is very polar with a dipole moment of 4.51 D for triphenylphosphine. The nature of the phosphorus to oxygen double bond is a matter of debate. Pentavalent phosphorus like nitrogen is not compatible with the octet rule. In older literature the bond is represented as a dative bond just like an amine oxide. The prevailing view is that of a full double bond with back bonding taking place between a filled oxygen electron pair and an empty phosphorus d-orbital (lacking in nitrogen). problem is: the P=O bond does not react as any C=C double bond as addition reactions are absent and involvement of a phosphorus d-orbital in bonding is not supported in silico. Alternative theories favor an ionic bond P+−O− which on its own strength should explain the short bond length. Molecular Orbital Theory proposes that the short bond length is attributed to the donation of the lone pair electrons from oxygen to the antibonding phosphorus-carbon bonds. This proposal is supported by ab initio calculations and has gained consensus in the chemistry community. Phosphines are easily oxidized to phosphine oxides as examplified by the directed synthesis of a phospha crown, the phosphorus analogue of an aza crown where it is not possible to isolate the phosphine itself. # Phosphonates Phosphonates have the general structure R−P(=O)(OR)2. In the Horner-Wadsworth-Emmons reaction and the Seyferth-Gilbert homologation phosphonates are used as stabilized carbanions in reactions with carbonyl compounds. Phosphonates have many technical applications and bisphosphonates are a class of drugs. # Phosphite and phosphate esters Phosphite esters or phosphites have the general structure P(OR)3 with oxidation state +3. Phosphites are employed in the Perkow reaction and the Arbusov reaction. Phosphate esters with the general structure P(=O)(OR)3 and oxidation state +5 are of great technological importance as flame retardant agents and plasticizers. Lacking a P−C bond, these compounds are technically not organophosphorus compounds. # Phosphoranes Phosphoranes have a −5 oxidation state (δ5λ5) with parent compound the non-stable phosphoran PH5 or λ5-phosphane (lambda 5 phosphane). Phosphorus ylides are unsaturated phosphoranes used in the Wittig reaction. # Phosphorus multiple bonds Many compounds exist with carbon phosphorus multiple bonds (P=C) as phosphaalkenes (R2C::PR) and phosphaalkynes (RC:::PR). In the compound phosphorine one carbon atom in benzene is replaced by phosphorus. The reactivity of phosphaalkenes is often compared to that of alkenes and not to that of imines. The reason is that the HOMO of phosphaalkenes is not the phosphorus lone pair (as in imines the amine lone pair) but the double bond. Therefore like alkenes, phosphaalkenes engage in Wittig reactions, Peterson reactions, Cope rearrangements and Diels-Alder reactions. The first phosphaalkene was synthesised in 1974 by Becker as a keto-enol tautomerism akin a Brook rearrangement: with R = methyl or phenyl and tms representing trimethylsilyl. In the same year Harold Kroto established spectroscopically that thermolysis of Me2PH yielded CH2=PMe. A general method for the synthesis of phosphaalkenes is by 1,2-elimination of suitable precursors, initiated thermally or by base such as DBU, DABCO or triethylamine: The Becker method is used in the synthesis of the phosphorus pendant of Poly(p-phenylene vinylene): Diphosphenes are compounds containing P=P phosphorus double bonds. Phosphazenes have a P=N double bond.

Inertial confinement fusion Inertial confinement fusion (ICF) is a process where nuclear fusion reactions are initiated by heating and compressing a fuel target, typically in the form of a pellet that most often contains a mixture of deuterium and tritium. To compress and heat the fuel, energy is delivered to the outer layer of the target using high-energy beams of laser light, electrons or ions, although for a variety of reasons, almost all ICF devices to date have used lasers. The heated outer layer explodes outward, producing a reaction force against the remainder of the target, accelerating it inwards, and sending shock waves into the center. A sufficiently powerful set of shock waves can compress and heat the fuel at the center so much that fusion reactions occur. The energy released by these reactions will then heat the surrounding fuel, which may also begin to undergo fusion. The aim of ICF is to produce a condition known as "ignition", where this heating process causes a chain reaction that burns a significant portion of the fuel. Typical fuel pellets are about the size of a pinhead and contain around 10 milligrams of fuel: in practice, only a small proportion of this fuel will undergo fusion, but if all this fuel was consumed it would release the energy equivalent to burning a barrel of oil. ICF is one of two major branches of fusion energy research, the other being magnetic confinement fusion. To date most of the work in ICF has been carried out in the United States, and generally has seen less development effort than magnetic approaches. When it was first proposed, ICF appeared to be a practical approach to fusion power production, but experiments during the 1970s and 80's demonstrated that the efficiency of these devices was much lower than expected. For much of the 1980s and 90s ICF experiments focused primarily on nuclear weapons research. More recent advances suggest that major gains in performance are possible, once again making ICF attractive for commercial power generation. A number of new experiments are underway or being planned to test this new "fast ignition" approach. # Description ## Basic fusion Fusion reactions combine lighter atoms, such as hydrogen, together to form larger ones. Generally the reactions take place at such high temperatures that the atoms have been ionized, their electrons stripped off by the heat; thus, fusion is typically described in terms of "nuclei" instead of "atoms". Nuclei are positively charged, and thus repel each other due to the electrostatic force. Counteracting this is the strong force which pulls nucleons together, but only at very short ranges. Thus a fluid of nuclei will generally not undergo fusion, the nuclei must be forced together before the strong force can pull them together into stable collections. Fusion reactions on a scale useful for energy production require a very large amount of energy to initiate in order to overcome the so-called Coulomb barrier or fusion barrier energy. Generally less energy will be needed to cause lighter nuclei to fuse, as they have less charge and thus a lower barrier energy, and when they do fuse, more energy will be released. As the mass of the nuclei increase, there is a point where the reaction no longer gives off net energy — the energy needed to overcome the energy barrier is greater than the energy released in the resulting fusion reaction. The key to practical fusion power is to select a fuel that requires the minimum amount of energy to start, that is, the lowest barrier energy. The best fuel from this standpoint is a one to one mix of deuterium and tritium; both are heavy isotopes of hydrogen. The D-T (deuterium & tritium) mix has a low barrier because of its high ratio of neutrons to protons. The presence of neutral neutrons in the nuclei helps pull them together via the strong force; while the presence of positively charged protons pushes the nuclei apart via Coloumbic forces (the electromagnetic force). Tritium has one of the highest ratios of neutrons to protons of any stable or moderately unstable nuclide -- two neutrons and one proton. Adding protons or removing neutrons increases the energy barrier. In order to create the required conditions, the fuel must be heated to tens of millions of degrees, and/or compressed to immense pressures. The temperature and pressure required for any particular fuel to fuse is known as the Lawson criterion. These conditions have been known since the 1950s when the first H-bombs were built. ## ICF mechanism of action In a "hydrogen bomb" the fusion fuel is compressed and heated with a separate fission bomb. A variety of mechanisms transfers the energy of the "trigger"'s explosion into the fusion fuel. The use of a nuclear bomb to ignite a fusion reaction makes the concept less than useful as a power source. Not only would the triggers be prohibitively expensive to produce, but there is a minimum size that such a bomb can be built, defined roughly by the critical mass of the plutonium fuel used. Generally it seems difficult to build nuclear devices smaller than about 1 kiloton in size, which would make it a difficult engineering problem to extract power from the resulting explosions. Also the smaller a thermonuclear bomb is, the "dirtier" it is, that is to say, the percentage of energy produced in the explosion by fusion is decreased while the percent produced by fission reactions tends toward unity (100%). This did not stop efforts to design such a system however, leading to the PACER concept. If some source of compression could be found, other than a nuclear bomb, then the size of the reaction could be scaled down. This idea has been of intense interest to both the bomb-making and fusion energy communities. It was not until the 1970s that a potential solution appeared in the form of very large, very high power, high energy lasers, which were then being built for weapons and other research. The D-T mix in such a system is known as a target, containing much less fuel than in a bomb design (often only micro or milligrams), and leading to a much smaller explosive force. Generally ICF systems use a single laser, the driver, whose beam is split up into a number of beams which are subsequently individually amplified by a trillion times or more. These are sent into the reaction chamber (called a target chamber) by a number of mirrors, positioned in order to illuminate the target evenly over its whole surface. The heat applied by the driver causes the outer layer of the target to explode, just as the outer layers of an H-bomb's fuel cylinder does when illuminated by the X-rays of the nuclear device. The material exploding off the surface causes the remaining material on the inside to be driven inwards with great force, eventually collapsing into a tiny near-spherical ball. In modern ICF devices the density of the resulting fuel mixture is as much as one-hundred times the density of lead, around 1000 g/cm³. This density is not high enough to create any useful rate of fusion on its own. However, during the collapse of the fuel, shock waves also form and travel into the center of the fuel at high speed. When they meet their counterparts moving in from the other sides of the fuel in the center, the density of that spot is raised much further. Given the correct conditions, the fusion rate in the region highly compressed by the shock wave can give off significant amounts of highly energetic alpha particles. Due to the high density of the surrounding fuel, they move only a short distance before being "thermalized", losing their energy to the fuel as heat. This additional energy will cause additional fusion reactions in the heated fuel, giving off more high-energy particles. This process spreads outward from the center, leading to a kind of self sustaining burn known as ignition. ## Issues with the successful achievement of ICF The primary problems with increasing ICF performance since the early experiments in the 1970s have been of energy delivery to the target, controlling symmetry of the imploding fuel, preventing premature heating of the fuel (before maximum density is achieved), preventing premature mixing of hot and cool fuel by hydrodynamic instabilities and the formation of a 'tight' shockwave convergence at the compressed fuel center. In order to focus the shock wave on the center of the target, the target must be made with extremely high precision and sphericity with aberrations of no more than a few micrometres over its surface (inner and outer). Likewise the aiming of the laser beams must be extremely precise and the beams must arrive at the same time at all points on the target. Beam timing is a relatively simple issue though and is solved by using delay lines in the beams' optical path to achieve picosecond levels of timing accuracy. The other major problem plaguing the achievement of high symmetry and high temperatures/densities of the imploding target are so called "beam-beam" imbalance and beam anisotropy. These problems are, respectively, where the energy delivered by one beam may be higher or lower than other beams impinging on the target and of "hot spots" within a beam diameter hitting a target which induces uneven compression on the target surface, thereby forming Rayleigh–Taylor instabilities in the fuel, prematurely mixing it and reducing heating efficacy at the time of maximum compression. All of these problems have been substantially mitigated to varying degrees in the past two decades of research by using various beam smoothing techniques and beam energy diagnostics to balance beam to beam energy though RT instability remains a major issue. Target design has also improved tremendously over the years. Modern cryogenic hydrogen ice targets tend to freeze a thin layer of deuterium just on the inside of a plastic sphere while irradiating it with a low power IR laser to smooth its inner surface while monitoring it with a microscope equipped camera, thereby allowing the layer to be closely monitored ensuring its "smoothness".. Cryogenic targets filled with a deuterium tritium (D-T) mixture are "self-smoothing" due to the small amount of heat created by the decay of the radioactive tritium isotope. This is often referred to as "beta-layering". Certain targets are surrounded by a small metal cylinder which is irradiated by the laser beams instead of the target itself, an approach known as "indirect drive". In this approach the lasers are focused on the inner side of the cylinder, heating it to a superhot plasma which radiates mostly in X-rays. The X-rays from this plasma are then absorbed by the target surface, imploding it in the same way as if it had been hit with the lasers directly. The absorption of thermal x-rays by the target is more efficient than the direct absorption of laser light, however these hohlraums or "burning chambers" also take up considerable energy to heat on their own thus significantly reducing the overall efficiency of laser-to-target energy transfer, they are thus a debated feature even today; the equally numerous "direct-drive" design does not use them. Most often, indirect drive hohlraum targets are used to simulate thermonuclear weapons tests due to the fact that the fusion fuel in them is also imploded mainly by X-ray radiation. A variety of ICF drivers are being explored. Lasers have improved dramatically since the 1970s, scaling up in energy and power from a few joules and kilowatts to megajoules (see NIF laser) and hundreds of terawatts, using mostly frequency doubled or tripled light from neodymium glass amplifiers. Heavy ion beams are particularly interesting for commercial generation, as they are easy to create, control, and focus. On the downside, it is very difficult to achieve the very high energy densities required to implode a target efficiently, and most ion-beam systems require the use of a hohlraum surrounding the target to smooth out the irradiation, reducing the overall efficiency of the coupling of the ion beam's energy to that of the imploding target further. # Brief history of ICF The first laser-driven "ICF" experiments (though strictly speaking, these were only high intensity laser-hydrogen plasma interaction experiments) were carried out using ruby lasers soon after these were invented in the 1960s. It was realized that the power available from existing lasers was far too low to be truly useful in achieving significant fusion reactions, but were useful in establishing preliminary theories describing high intensity light and plasma interactions. A major step in the ICF program took place in 1972, when John Nuckolls of the Lawrence Livermore National Laboratory (LLNL) published a seminal article in Nature that predicted that ignition could be achieved with laser energies about 1 kJ, while "high gain" would require energies around 1 MJ. The primary problems in making a practical ICF device would be building a laser of the required energy and making its beams uniform enough to collapse a fuel target evenly. At first it was not obvious that the energy issue could ever be addressed, but a new generation of laser devices first invented in the late 1960s pointed to ways to build devices of the required power. Starting in the early-1970s several labs started experiments with such devices, including krypton fluoride excimer lasers at the Naval Research Laboratory (NRL) and the solid-state lasers (Nd:glass lasers) at Lawrence Livermore National Laboratory (LLNL). What followed was a series of advances followed by seemingly intractable problems that characterized fusion research in general. High energy ICF experiments (multi hundred joules per shot and greater experiments) began in earnest in the early-1970s, when lasers of the required energy and power were first designed. This was some time after the successful design of magnetic confinement fusion systems, and around the time of the particularly successful tokamak design that was introduced in the early '70s. Nevertheless, high funding for fusion research stimulated by the multiple energy crises during the mid to late 1970s produced rapid gains in performance, and inertial designs were soon reaching the same sort of "below breakeven" conditions of the best magnetic systems. LLNL was, in particular, very well funded and started a major laser fusion development program. Their Janus laser started operation in 1974, and validated the approach of using Nd:glass lasers to generate very high power devices. Focusing problems were explored in the Long path laser and Cyclops laser, which led to the larger Argus laser. None of these were intended to be practical ICF devices, but each one advanced the state of the art to the point where there was some confidence the basic approach was valid. At the time it was believed that making a much larger device of the Cyclops type could both compress and heat the ICF targets, leading to ignition in the "short term". This was a misconception based on extrapolation of the fusion yields seen from experiments utilizing the so called "exploding pusher" type of fuel capsules. During the period spanning the years of the late 70's and early 80's the estimates for laser energy on target needed to achieve ignition doubled almost yearly as the various plasma instabilities and laser-plasma energy coupling loss modes were gradually understood. The realization that the simple exploding pusher target designs and mere few kilojoule (kJ) laser irradiation intensities would never scale to high gain fusion yields led to the effort to increase laser energies to the hundred kJ level in the UV and to the production of advanced ablator and cryogenic DT ice target designs. One of the earliest serious and large scale attempts at an ICF driver design was the Shiva laser, a 20-beam neodymium doped glass laser system built at the Lawrence Livermore National Laboratory (LLNL) that started operation in 1978. Shiva was a "proof of concept" design intended to demonstrate compression of fusion fuel capsules to many times the liquid density of hydrogen. In this, Shiva succeeded and compressed its pellets to 100 times the liquid density of deuterium. However, due to the laser's strong coupling with hot electrons, premature heating of the dense plasma (ions) was problematic and fusion yields were low. This failure by Shiva to efficiently heat the compressed plasma pointed to the use of optical frequency multipliers as a solution which would frequency triple the infrared light from the laser into the ultraviolet at 351 nm. Newly discovered schemes to efficiently frequency triple high intensity laser light discovered at the Laboratory for Laser Energetics in 1980 enabled this method of target irradiation to be experimented with in the 24 beam OMEGA laser and the NOVETTE laser, which was followed by the Nova laser design with 10 times the energy of Shiva, the first design with the specific goal of reaching ignition conditions. Nova also failed in its goal of achieving ignition, this time due to severe variation in laser intensity in its beams (and differences in intensity between beams) caused by filamentation which resulted in large non-uniformity in irradiation smoothness at the target and asymmetric implosion. The techniques pioneered earlier could not address these new issues. But again this failure led to a much greater understanding of the process of implosion, and the way forward again seemed clear, namely the increase in uniformity of irradiation, the reduction of hot-spots in the laser beams through beam smoothing techniques to reduce Rayleigh–Taylor instability imprinting on the target and increased laser energy on target by at least an order of magnitude. Funding for fusion research was severely constrained in the 80's, but Nova nevertheless successfully gathered enough information for a next generation machine. The resulting design, now known as the National Ignition Facility, started construction at LLNL in 1997. NIF's main objective will be to operate as the flagship experimental device of the so called nuclear stewardship program, supporting LLNLs traditional bombmaking role. Originally intended to start construction in the early 1990s, NIF is now scheduled for fusion experiments starting in 2009 when the remaining lasers in the 192-beam array are installed. As of November 2007, ninety-six of the lasers have been completed and commissioned. The first credible attempts at ignition are scheduled for 2010. A more recent development is the concept of "fast ignition", which may offer a way to directly heat the high density fuel after compression, thus decoupling the heating and compression phases of the implosion. In this approach the target is first compressed "normally" using a driver laser system, and then when the implosion reaches maximum density (at the stagnation point or "bang time"), a second ultra-short pulse ultra-high power petawatt (PW) laser delivers a single pulse focussed on one side of the core, dramatically heating it and hopefully starting fusion ignition. The two types of fast ignition are the "plasma bore-through" method and the "cone-in-shell" method. In the first method the petawatt laser is simply expected to bore straight through the outer plasma of an imploding capsule and to impinge on and heat the dense core, whereas in the cone-in-shell method, the capsule is mounted on the end of a small high-z cone such that the tip of the cone projects into the core of the capsule. In this second method, when the capsule is imploded, the petawatt has a clear view straight to the high density core and does not have to waste energy boring through a 'corona' plasma; however, the presence of the cone affects the implosion process in significant ways that are not fully understood. Several projects are currently underway to explore the fast ignition approach, including upgrades to the OMEGA laser at the University of Rochester, the GEKKO XII device in Japan, and an entirely new £500m facility, known as HiPER, proposed for construction in the European Union. If successful, the fast ignition approach could dramatically lower the total amount of energy needed to be delivered to the target; whereas NIF uses UV beams of 2 MJ, HiPER's driver is 200 kJ and heater 70 kJ, yet the predicted fusion gains are nevertheless even higher than on NIF. Finally, using a different approach entirely is the z-pinch device. Z-pinch uses massive amounts of electrical current which is switched into a small number of extremely fine wires. The wires heat and vaporize so quickly they fill the target with x-rays, which implode the fuel pellet. In order to direct the x-rays onto the pellet the target consists of a cylindrical metal capsule with the wiring and fuel within. Challenges to this approach include relatively low drive temperatures, resulting in slow implosion velocities and potentially large instability growth, and preheat caused by high-energy x-rays. # Inertial confinement fusion as an energy source Practical power plants built using ICF have been studied since the late 1970s when ICF experiments were beginning to ramp up to higher powers; they are known as inertial fusion energy, or IFE plants. These devices would deliver a successive stream of targets to the reaction chamber, several a second typically, and capture the resulting heat and neutron radiation from their implosion and fusion to drive a conventional steam turbine. Laser driven systems were initially believed to be able to generate commercially useful amounts of energy. However, as estimates of the energy required to reach ignition grew dramatically during the 1970s and '80s, these hopes were abandoned. Given the low efficiency of the laser amplification process (about 1 to 1.5%), and the losses in generation (steam-driven turbine systems are typically about 35% efficient), fusion gains would have to be on the order of 350 just to break even. These sorts of gains appeared to be impossible to generate, and ICF work turned primarily to weapons research. With the recent introduction of fast ignition, things have changed dramatically. In this approach gains of 100 are predicted in the first experimental device, HiPER. Given a gain of about 100 and a laser efficiency of about 1%, HiPER produces about the same amount of fusion energy as electrical energy was needed to create it. Additionally newer laser devices appear to be able to greatly improve driver efficiency. Current designs use xenon flash lamps to produce an intense flash of white light, some of which is absorbed by the Nd:glass that produces the laser power. In total about 1 to 1.5% of the electrical power fed into the flash tubes is turned into useful laser light. Newer designs replace the flash lamps with laser diodes that are tuned to produce most of their energy in a frequency range that is strongly absorbed. Initial experimental devices offer efficiencies of about 10%, and it is suggested that 20% is a real possibility with some additional development. With "classical" devices like NIF about 330 MJ of electrical power are used to produce the driver beams, producing an expected yield of about 20 MJ, with the maximum credible yield of 45 MJ. Using the same sorts of numbers in a reactor combining fast ignition with newer lasers would offer dramatically improved performance. HiPER requires about 270 kJ of laser energy, so assuming a first-generation diode laser driver at 10% the reactor would require about 3 MJ of electrical power. This is expected to produce about 30 MJ of fusion power. Even a very poor conversion to electrical energy appears to offer real-world power output, and incremental improvements in yield and laser efficiency appear to be able to offer a commercially useful output. ICF systems face some of the same secondary power extraction problems as magnetic systems in generating useful power from their reactions. One of the primary concerns is how to successfully remove heat from the reaction chamber without interfering with the targets and driver beams. Another serious concern is that the huge number of neutrons released in the fusion reactions react with the plant, causing them to become intensely radioactive themselves, as well as mechanically weakening metals. Fusion plants built of conventional metals like steel would have a fairly short lifetime and the core containment vessels will have to be replaced frequently. One current concept in dealing with both of these problems, as shown in the HYLIFE-II baseline design, is to use a "waterfall" of flibe, a molten mix of fluorine, lithium and beryllium salts, which both protect the chamber from neutrons, as well as carrying away heat. The flibe is then passed into a heat exchanger where it heats water for use in the turbines. Another, Sombrero, uses a reaction chamber built of carbon fibre which has a very low neutron cross section. Cooling is provided by a molten ceramic, chosen because of its ability to stop the neutrons from traveling any further, while at the same time being an efficient heat transfer agent. As a power source, even the best IFE reactors would be hard-pressed to deliver the same economics as coal, although they would have advantages in terms of less pollution and global warming. Coal can simply be dug up and burned for little financial cost, one of the main costs being shipping. In terms of the turbomachinery and generators, an IFE plant would likely cost the same as a coal plant of similar power, and one might suggest that the "combustion chamber" in an IFE plant would be similar to those for a coal plant. On the other hand, a coal plant has no equivalent to the driver laser, which would make the IFE plant much more expensive. Additionally, extraction of deuterium and its formation into useful fuel pellets is considerably more expensive than coal processing, although the cost of shipping it is much lower (in terms of energy per unit mass). It is generally estimated that an IFE plant would have long-term operational costs about the same as coal, discounting development. HYLIFE-II claims to be about 40% less expensive than a coal plant of the same size, but considering the problems with NIF, it is simply too early to tell if this is realistic or not. The various phases of such a project are the following, the sequence of inertial confinement fusion development follows much the same outline: - burning demonstration: reproducible achievement of some fusion energy release (not necessarily a Q factor of >1). - high gain demonstration: experimental demonstration of the feasibility of a reactor with a sufficient energy gain. - industrial demonstration: validation of the various technical options, and of the whole data needed to define a commercial reactor. - commercial demonstration: demonstration of the reactor ability to work over a long period, while respecting all the requirements for safety, liability and cost. At the moment, according to the available data , inertial confinement fusion experiments have not gone beyond the first phase, although Nova and others have repeatedly demonstrated operation within this realm. In the short term a number of new systems are expected to reach the second stage. NIF is expected to be able to quickly reach this sort of operation when it starts, but the date for the start of fusion experiments is currently suggested to be somewhere between 2010 and 2014. Laser Mégajoule would also operate within the second stage, and was initially expected to become operational in 2010. Fast ignition systems work well within this range. Finally, the z-pinch machine, not using lasers, is expected to obtain a high fusion energy gain, as well as capability for repetitive working, starting around 2010. For a true industrial demonstration, further work is required. In particular, the laser systems need to be able to run at high operating frequencies, perhaps one to ten times a second. Most of the laser systems mentioned in this article have trouble operating even as much as once a day. Parts of the HiPER budget are dedicated to research in this direction as well. Because they convert electricity into laser light with much higher efficiency, diode lasers also run cooler, which in turn allows them to be operated at much higher frequencies. HiPER is currently studying devices that operate at 1 MJ at 1 Hz, or alternately 100 kJ at 10 Hz. # Inertially confined fusion and the nuclear weapons program The very hot and dense conditions encountered during an Inertial Confinement Fusion experiment are similar to those created in a thermonuclear weapon, and have applications to the nuclear weapons program. ICF experiments might be used, for example, to help determine how warhead performance will degrade as it ages, or as part of a program of designing new weapons. Retaining knowledge and corporate expertise in the nuclear weapons program is another motivation for pursuing ICF.. Funding for the NIF facility in the United States is sourced from the 'Nuclear Weapons Stewardship' program, and the goals of the program are oriented accordingly. It has been argued that some aspects of ICF research may violate the Comprehensive Test Ban Treaty or the Nuclear Non-Proliferation Treaty.. In the long term, despite the formidable technical hurdles, ICF research might potentially lead to the creation of a "pure fusion weapon". # Inertial confinement fusion as a neutron source Inertial confinement fusion has the potential to produce orders of magnitude more neutrons than spallation. Neutrons are capable of locating hydrogen atoms in molecules, resolving atomic thermal motion and studying collective excitations of photons more effectively than X-rays. Neutron scattering studies of molecular structures could resolve problems associated with protein folding, diffusion through membanes, proton transfer mechanisms, dynamics of molecular motors, etc. by modulating thermal neutrons into beams of slow neutrons .

Pyrimethamine # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Pyrimethamine is a folic acid antagonist that is FDA approved for the treatment of toxoplasmosis, acute malaria and for the prophylaxis of malaria. Common adverse reactions include rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Pyrimethamine is indicated for the treatment of toxoplasmosis when used conjointly with a sulfonamide, since synergism exists with this combination. - Concurrent administration of folinic acid is strongly recommended in all patients. - Starting dose is 50 to 75 mg of the drug daily, together with 1 to 4 g daily of a sulfonamide of the sulfapyrimidine type, e.g. sulfadoxine; for 1 to 3 weeks. - The dosage may then be reduced to about one half that previously given for each drug and continued for an additional 4 to 5 weeks. - Pyrimethamine is also indicated for the treatment of acute malaria. It should not be used alone to treat acute malaria. Fast-acting schizonticides such as chloroquine or quinine are indicated and preferable for the treatment of acute malaria. However, conjoint use of pyrimethamine with a sulfonamide (e.g., sulfadoxine) will initiate transmission control and suppression of susceptible strains of plasmodia. - Dosage: 25 mg daily for 2 days with a sulfonamide will initiate transmission control and suppression of non-falciparum malaria. - Pyrimethamine is indicated for the chemoprophylaxis of malaria due to susceptible strains of plasmodia. However, resistance to pyrimethamine is prevalent worldwide. It is not suitable as a prophylactic agent for travelers to most areas. - Dosage: 25 mg (1 tablet) once weekly ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pyrimethamine in adult patients. ### Non–Guideline-Supported Use - Prophylaxis of Pneumocystis jiroveci pneumonia infection in HIV-infected adults - Prophylaxis of Toxoplasma gondii encephalitis in adults and adolescents with human immunodeficiency virus # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Pyrimethamine is indicated for the treatment of toxoplasmosis when used conjointly with a sulfonamide, since synergism exists with this combination. - Concurrent administration of folinic acid is strongly recommended in all patients. - Dosage: - 1 mg/kg/day divided into 2 equal daily doses for 2 to 4 days - This dose may be reduced to one half and continued for approximately 1 month. - Pyrimethamine is also indicated for the treatment of acute malaria. It should not be used alone to treat acute malaria. Fast-acting schizonticides such as chloroquine or quinine are indicated and preferable for the treatment of acute malaria. However, conjoint use of pyrimethamine with a sulfonamide (e.g., sulfadoxine) will initiate transmission control and suppression of susceptible strains of plasmodia. - Dosage for children 4 through 10 years old: may be given 25 mg daily for 2 days - Pyrimethamine is indicated for the chemoprophylaxis of malaria due to susceptible strains of plasmodia. However, resistance to pyrimethamine is prevalent worldwide. It is not suitable as a prophylactic agent for travelers to most areas. - Dosage: - Pediatric patients over 10 years: 25 mg (1 tablet) once weekly - Children 4 through 10 years: 12.5 mg (1/2 tablet) once weekly - Infants and children under 4 years: 6.25 mg (1/4 tablet) once weekly. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pyrimethamine in pediatric patients. ### Non–Guideline-Supported Use - Prophylaxis of Toxoplasma gondii encephalitis in adults and adolescents with human immunodeficiency virus. # Contraindications - Use of pyrimethamine is contraindicated in patients with known hypersensitivity to pyrimethamine or to any component of the formulation. - Use of the drug is also contraindicated in patients with documented megaloblastic anemia due to folate deficiency. # Warnings - The dosage of pyrimethamine required for the treatment of toxoplasmosis is 10 to 20 times the recommended antimalaria dosage and approaches the toxic level. If signs of folate deficiency develop, reduce the dosage or discontinue the drug according to the response of the patient. Folinic acid (leucovorin) should be administered in a dosage of 5 to 15 mg daily (orally, IV, or IM) until normal hematopoiesis is restored. - Data in 2 humans indicate that pyrimethamine may be carcinogenic; a 51-year-old female who developed chronic granulocytic leukemia after taking pyrimethamine for 2 years for toxoplasmosis and a 56-year-old patient who developed reticulum cell sarcoma after 14 months of pyrimethamine for toxoplasmosis. - Pyrimethamine has been reported to produce a significant increase in the number of lung tumors in mice when given intraperitoneally at doses of 25 mg/kg. - Pyrimethamine susceptible to adverse effects from an overdose. Deaths in pediatric patients have been reported after accidental ingestion. # Adverse Reactions ## Clinical Trials Experience Hypersensitivity reactions, occasionally severe (such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and anaphylaxis), and hyperphenylalaninemia, can occur particularly when pyrimethamine is administered concomitantly with a sulfonamide. Consult the complete prescribing information for the relevant sulfonamide for sulfonamide-associated adverse events. With doses of pyrimethamine used for the treatment of toxoplasmosis, anorexia and vomiting may occur. Vomiting may be minimized by giving the medication with meals; it usually disappears promptly upon reduction of dosage. Doses used in toxoplasmosis may produce megaloblastic anemia, leukopenia, thrombocytopenia, pancytopenia, atrophic glossitis, hematuria, and disorders of cardiac rhythm. Hematologic effects, however, may also occur at low doses in certain individuals. Pulmonary eosinophilia has been reported rarely. ## Postmarketing Experience There is limited information regarding Pyrimethamine Postmarketing Experience in the drug label. # Drug Interactions - Pyrimethamine may be used with sulfonamides, quinine and other antimalarials, and with other antibiotics. However, the concomitant use of other antifolic drugs or agents associated with myelosuppression including sulfonamides or trimethoprim-sulfamethoxazole combinations, proguanil, zidovudine, or cytostatic agents (e.g., methotrexate), while the patient is receiving pyrimethamine, may increase the risk of bone marrow suppression. - If signs of folate deficiency develop, pyrimethamine should be discontinued. Folinic acid (leucovorin) should be administered until normal hematopoiesis is restored. - Mild hepatotoxicity has been reported in some patients when lorazepam and pyrimethamine were administered concomitantly. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Pyrimethamine has been shown to be teratogenic in rats when given in oral doses 7 times the human dose for chemoprophylaxis of malaria or 2.5 times the human dose for treatment of toxoplasmosis. At these doses in rats, there was a significant increase in abnormalities such as cleft palate, brachygnathia, oligodactyly, and microphthalmia. Pyrimethamine has also been shown to produce terata such as meningocele in hamsters and cleft palate in miniature pigs when given in oral doses 170 and 5 times the human dose, respectively, for chemoprophylaxis of malaria or for treatment of toxoplasmosis. There are no adequate and well-controlled studies in pregnant women. pyrimethamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Concurrent administration of folinic acid is strongly recommended when used for the treatment of toxoplasmosis during pregnancy. Pregnancy Category (AUS): B3 There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pyrimethamine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Pyrimethamine during labor and delivery. ### Nursing Mothers Pyrimethamine is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from pyrimethamine and from concurrent use of a sulfonamide with pyrimethamine for treatment of some patients with toxoplasmosis, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use There is no FDA guidance on the use of Pyrimethamine in pediatric settings. ### Geriatic Use Clinical studies of pyrimethamine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Pyrimethamine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Pyrimethamine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Pyrimethamine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Pyrimethamine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Pyrimethamine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Pyrimethamine in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring In patients receiving high dosage, as for the treatment of toxoplasmosis, semiweekly blood counts, including platelet counts, should be performed. # IV Compatibility There is limited information regarding the compatibility of Pyrimethamine and IV administrations. # Overdosage Following the ingestion of 300 mg or more of pyrimethamine, gastrointestinal and/or central nervous system signs may be present, including convulsions. The initial symptoms are usually gastrointestinal and may include abdominal pain, nausea, severe and repeated vomiting, possibly including hematemesis. Central nervous system toxicity may be manifest by initial excitability, generalized and prolonged convulsions which may be followed by respiratory depression, circulatory collapse, and death within a few hours. Neurological symptoms appear rapidly (30 minutes to 2 hours after drug ingestion), suggesting that in gross overdosage pyrimethamine has a direct toxic effect on the central nervous system. The fatal dose is variable, with the smallest reported fatal single dose being 375 mg. There are, however, reports of pediatric patients who have recovered after taking 375 to 625 mg. There is no specific antidote to acute pyrimethamine poisoning. In the event of overdosage, symptomatic and supportive measures should be employed. Gastric lavage is recommended and is effective if carried out very soon after drug ingestion. Parenteral diazepam may be used to control convulsions. Folinic acid should be administered within 2 hours of drug ingestion to be most effective in counteracting the effects on the hematopoietic system. Due to the long half-life of pyrimethamine, daily monitoring of peripheral blood counts is recommended for up to several weeks after the overdose until normal hematologic values are restored. # Pharmacology ## Mechanism of Action Binds to and reversibly inhibits the protozoal enzyme dihydrofolate reductase, selectively blocking conversion of dihydrofolic acid to its functional form, tetrahydrofolic acid. This depletes folate, an essential cofactor in the biosynthesis of nucleic acids, resulting in interference with protozoal nucleic acid and protein production. ## Structure Pyrimethamine, known chemically as 5-(4-chlorophenyl)-6-ethyl-2,4-pyrimidinediamine, has the following structural formula: ## Pharmacodynamics Pyrimethamine is a folic acid antagonist and the rationale for its therapeutic action is based on the differential requirement between host and parasite for nucleic acid precursors involved in growth. This activity is highly selective against plasmodia and Toxoplasma gondii. Pyrimethamine possesses blood schizonticidal and some tissue schizonticidal activity against malaria parasites of humans. However, the 4-amino-quinoline compounds are more effective against the erythrocytic schizonts. It does not destroy gametocytes, but arrests sporogony in the mosquito. The action of pyrimethamine against Toxoplasma gondii is greatly enhanced when used in conjunction with sulfonamides. This was demonstrated by Eyles and Coleman1 in the treatment of experimental toxoplasmosis in the mouse. Jacobs et al2 demonstrated that combination of the 2 drugs effectively prevented the development of severe uveitis in most rabbits following the inoculation of the anterior chamber of the eye with toxoplasma. ## Pharmacokinetics Pyrimethamine is well absorbed with peak levels occurring between 2 to 6 hours following administration. It is eliminated slowly and has a plasma half-life of approximately 96 hours. Pyrimethamine is 87% bound to human plasma proteins. ## Nonclinical Toxicology Data in 2 humans indicate that pyrimethamine may be carcinogenic; a 51-year-old female who developed chronic granulocytic leukemia after taking pyrimethamine for 2 years for toxoplasmosis and a 56-year-old patient who developed reticulum cell sarcoma after 14 months of pyrimethamine for toxoplasmosis. Pyrimethamine has been reported to produce a significant increase in the number of lung tumors in mice when given intraperitoneally at doses of 25 mg/kg. In vivo, chromosomes analyzed from the bone marrow of rats dosed with pyrimethamine showed an increased number of structural and numerical aberrations. # Clinical Studies There is limited information regarding Pyrimethamine Clinical Studies in the drug label. # How Supplied - Pyrimethamine 25 mg tablets - Bottles of 100 - NDC 52054-330-10 and NDC 52054-330-95 ## Storage Store at 15° to 25°C (59° to 77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be warned that at the first appearance of a skin rash they should stop use of pyrimethamine and seek medical attention immediately. Patients should also be warned that the appearance of sore throat, pallor, purpura, or glossitis may be early indications of serious disorders which require treatment with pyrimethamine to be stopped and medical treatment to be sought. - Women of childbearing potential who are taking pyrimethamine should be warned against becoming pregnant. Patients should be warned to keep pyrimethamine out of the reach of children. Patients should be advised not to exceed recommended doses. Patients should be warned that if anorexia and vomiting occur, they may be minimized by taking the drug with meals. - Concurrent administration of folinic acid is strongly recommended when used for the treatment of toxoplasmosis in all patients. # Precautions with Alcohol Alcohol-Pyrimethamine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Daraprim # Look-Alike Drug Names There is limited information regarding Pyrimethamine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price

Chemosensor A chemosensor, also known as chemoreceptor, is a cell or group of cells that transduce a chemical signal into an action potential. Or, more generally, a chemosensor detects certain chemical stimuli in the environment. # Classes There are two main classes of the chemosensor: direct and distance. - Examples of distance chemoreceptors are: -lfactory receptor neurons in the olfactory system neurons in the vomeronasal organ that detect pheromones - olfactory receptor neurons in the olfactory system - neurons in the vomeronasal organ that detect pheromones - Examples of direct chemoreceptors include taste buds in the gustatory system carotid bodies and aortic bodies that detect changes in pH inside the body. - taste buds in the gustatory system - carotid bodies and aortic bodies that detect changes in pH inside the body. # Systems affected ## Breathing rate Chemoreceptors detect the levels of carbon dioxide in the blood. To do this, they monitor the concentration of hydrogen ions in the blood, which decreases the pH of the blood, as a direct consequence of the raised carbon dioxide concentration. The response is that the inspiratory centre (in the medulla), sends nervous impulses to the external intercostal muscles and the diaphragm, via the phrenic nerve to increase breathing rate and the volume of the lungs during inhalation. Chemoreceptors which affect breathing rate are broken down into two categories. - central chemoreceptors (in the medulla) do not respond to a drop in oxygen, and eventually desensitize. - peripheral chemoreceptors (carotid arteries and aorta) do respond to extreme drops in oxygen, and do not desensitize. Their effect on breathing rate is less than that of the central chemoreceptors. ## Heart rate Chemoreceptors in the medulla oblongata, carotid arteries and aortic arch, detect the levels of carbon dioxide in the blood, in the same way as applicable in the Breathing Rate section. In response to this high concentration, a nervous impulse is sent to the cardiovascular centre in the medulla, which will then feedback to the sympathetic ganglia, increasing nervous impulses here, and prompting the sinoatrial node to stimulate more contractions of the myogenic cardiac muscle increase heart rate. ## Sense organs In taste sensation, the tongue is composed of 5 different taste buds: salty, sour, sweet, bitter, and savory. The salty and sour tastes work directly through the ion channels, the sweet and bitter taste work through G protein-coupled receptors, and the savoury sensation is activated by glutamate. Noses in vertebrates and antennae in many invertebrates act as distance chemoreceptors. Molecules diffused through the air and bind to specific receptors on olfactory sensory neurons, activating an opening ion channel via G-proteins. When inputs from the environment are significant to the survival of the organism the input must be detected. As all life processes are ultimately based on chemistry it is natural that detection and passing on of the external input will involve chemical events. The chemistry of the environment is, of course, relevant to survival, and detection of chemical input from the outside may well articulate directly with cell chemicals. For example: The emissions of a predator's food source, such as odors or pheromones, may be in the air or on a surface where the food source has been. Cells in the head, usually the air passages or mouth, have chemical receptors on their surface that change when in contact with the emissions. The change does not stop there. It passes in either chemical or electrochemical form to the central processor, the brain or spinal cord. The resulting output from the CNS (central nervous system) makes body actions that will engage the food and enhance survival.

Intrapartum care for healthy women and babies This guideline covers the care of healthy women and their babies, during labour and immediately after the birth. It focuses on women who give birth between 37 and 42 weeks of pregnancy (‘term’). The guideline helps women to make an informed choice about where to have their baby. It also aims to reduce variation in aspects of care. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Place of birth ## Choosing planned place of birth Explain to both multiparous and nulliparous women who are at low risk of complications that giving birth is generally very safe for both the woman and her baby. Explain to both multiparous and nulliparous women that they may choose any birth setting (home, freestanding midwifery unit, alongside midwifery unit or obstetric unit), and support them in their choice of setting wherever they choose to give birth: Advise low‑risk multiparous women that planning to give birth at home or in a midwifery‑led unit (freestanding or alongside) is particularly suitable for them because the rate of interventions is lower and the outcome for the baby is no different compared with an obstetric unit. Advise low‑risk nulliparous women that planning to give birth in a midwifery‑led unit (freestanding or alongside) is particularly suitable for them because the rate of interventions is lower and the outcome for the baby is no different compared with an obstetric unit. Explain that if they plan birth at home there is a small increase in the risk of an adverse outcome for the baby. Using table 1 and table 2, explain to low‑risk multiparous women that: planning birth at home or in a freestanding midwifery unit is associated with a higher rate of spontaneous vaginal birth than planning birth in an alongside midwifery unit, and these 3 settings are associated with higher rates of spontaneous vaginal birth than planning birth in an obstetric unit planning birth in an obstetric unit is associated with a higher rate of interventions, such as instrumental vaginal birth, caesarean section and episiotomy, compared with planning birth in other settings there are no differences in outcomes for the baby associated with planning birth in any setting. Home (number of incidences per 1,000 multiparous women giving birth) Freestanding midwifery unit (number of incidences per 1,000 multiparous women giving birth) Alongside midwifery unit (number of incidences per 1,000 multiparous women giving birth) Obstetric unit (number of 1,000 incidences per multiparous women giving birth) Spontaneous vaginal birth Transfer to an obstetric unit Regional analgesia (epidural and/or spinal)* Episiotomy Caesarean birth Instrumental birth (forceps or ventouse) Blood transfusion - Figures from Birthplace 2011 and Blix et al. 2012 (all other figures from Birthplace 2011). Estimated transfer rate from an obstetric unit to a different obstetric unit owing to lack of capacity or expertise. * Blix reported epidural analgesia and Birthplace reported spinal or epidural analgesia. Outcomes Home (number of babies per 1,000 births) Freestanding midwifery unit (number of babies per 1,000 births) Alongside midwifery unit (number of babies per 1,000 births) Obstetric unit (number of babies per 1,000 births) Babies without serious medical problems Babies with serious medical problems* - Serious medical problems were combined in the study: neonatal encephalopathy and meconium aspiration syndrome were the most common adverse events, together accounting for 75% of the total. Stillbirths after the start of care in labour and death of the baby in the first week of life accounted for 13% of the events. Fractured humerus and clavicle were uncommon outcomes (less than 4% of adverse events). For the frequency of these events (how often any of them actually occurred), see appendix A. Using table 3 and table 4, explain to low‑risk nulliparous women that: planning birth at home or in a freestanding midwifery unit is associated with a higher rate of spontaneous vaginal birth than planning birth in an alongside midwifery unit, and these 3 settings are associated with higher rates of spontaneous vaginal birth than planning birth in an obstetric unit planning birth in an obstetric unit is associated with a higher rate of interventions, such as instrumental vaginal birth, caesarean section and episiotomy, compared with planning birth in other settings there are no differences in outcomes for the baby associated with planning birth in an alongside midwifery unit, a freestanding midwifery unit or an obstetric unit planning birth at home is associated with an overall small increase (about 4 more per 1,000 births) in the risk of a baby having a serious medical problem compared with planning birth in other settings. Home (number of incidences per 1,000 nulliparous women giving birth) Freestanding midwifery unit (number of incidences per 1,000 nulliparous women giving birth) Alongside midwifery unit (number of incidences per 1,000 nulliparous women giving birth) Obstetric unit (number of incidences per 1,000 nulliparous women giving birth) Spontaneous vaginal birth Transfer to an obstetric unit Regional analgesia (epidural and/or spinal)* Episiotomy Caesarean birth Instrumental birth (forceps or ventouse) Blood transfusion - Figures from Birthplace 2011 and Blix et al. 2012 (all other figures from Birthplace 2011). Estimated transfer rate from an obstetric unit to a different obstetric unit owing to lack of capacity or expertise. * Blix reported epidural analgesia and Birthplace reported spinal or epidural analgesia. Outcomes Home (number of babies per 1,000 births) Freestanding midwifery unit (number of babies per 1,000 births) Alongside midwifery unit (number of babies per 1,000 births) Obstetric unit (number of babies per 1,000 births) Babies without serious medical problems Babies with serious medical problems* - Serious medical problems were combined in the study: neonatal encephalopathy and meconium aspiration syndrome were the most common adverse events, together accounting for 75% of the total. Stillbirths after the start of care in labour and death of the baby in the first week of life accounted for 13% of the events. Fractured humerus and clavicle were uncommon outcomes – less than 4% of adverse events. For the frequency of these events (how often any of them actually occurred), see appendix A. Ensure that all healthcare professionals involved in the care of pregnant women are familiar with the types and frequencies of serious medical problems that can affect babies (see appendix A), in order to be able to provide this information to women if they request it. Commissioners and providers (this can also include networks of providers) should ensure that all 4 birth settings are available to all women (in the local area or in a neighbouring area). Give the woman the following information, including local statistics, about all local birth settings: Access to midwives, including: the likelihood of being cared for in labour by a familiar midwife the likelihood of receiving one‑to‑one care throughout labour (not necessarily being cared for by the same midwife for the whole of labour). Access to medical staff (obstetric, anaesthetic and neonatal). Access to pain relief, including birthing pools, Entonox, other drugs and regional analgesia. The likelihood of being transferred to an obstetric unit (if this is not the woman's chosen place of birth), the reasons why this might happen and the time it may take. Refer to table 5 if no local data are available. Primary reason for transfer to an obstetric unit* Number of women transferred from home (n=3,529) Number of women transferred from a freestanding midwifery unit (n=2,457) Number of women transferred from an alongside midwifery unit (n=4,401) Delay during first or second stage of labour Abnormal fetal heart rate Request for regional analgesia Meconium staining Retained placenta Repair of perineal trauma Neonatal concerns (postpartum) Other - Main reason for transfer to an obstetric unit for each woman (there may be more than 1 reason). If further discussion is wanted by either the midwife or the woman about the choice of planned place of birth, arrange this with a consultant midwife or supervisor of midwives, and/or a consultant obstetrician if there are obstetric issues. When discussing the woman's choice of place of birth with her, do not disclose personal views or judgements about her choices. Use tables 6, 7, 8 and 9 as part of an assessment for a woman choosing her planned place of birth: Table 6 and table 7 show medical conditions or situations in which there is increased risk for the woman or baby during or shortly after labour, where care in an obstetric unit would be expected to reduce this risk. The factors listed in table 8 and table 9 are not reasons in themselves for advising birth within an obstetric unit, but indicate that further consideration of birth setting may be required. Discuss these risks and the additional care that can be provided in the obstetric unit with the woman so that she can make an informed choice about planned place of birth. Disease area Medical condition Cardiovascular Confirmed cardiac disease Hypertensive disorders Respiratory Asthma requiring an increase in treatment or hospital treatment Cystic fibrosis Haematological Haemoglobinopathies – sickle‑cell disease, beta‑thalassaemia major History of thromboembolic disorders Immune thrombocytopenia purpura or other platelet disorder or platelet count below 100×109/litre Von Willebrand's disease Bleeding disorder in the woman or unborn baby Atypical antibodies which carry a risk of haemolytic disease of the newborn Endocrine Hyperthyroidism Diabetes Infective Risk factors associated with group B streptococcus whereby antibiotics in labour would be recommended Hepatitis B/C with abnormal liver function tests Carrier of/infected with HIV Toxoplasmosis – women receiving treatment Current active infection of chicken pox/rubella/genital herpes in the woman or baby Tuberculosis under treatment Immune Systemic lupus erythematosus Scleroderma Renal Abnormal renal function Renal disease requiring supervision by a renal specialist Neurological Epilepsy Myasthenia gravis Previous cerebrovascular accident Gastrointestinal Liver disease associated with current abnormal liver function tests Psychiatric Psychiatric disorder requiring current inpatient care Factor Additional information Previous complications Unexplained stillbirth/neonatal death or previous death related to intrapartum difficulty Previous baby with neonatal encephalopathy Pre‑eclampsia requiring preterm birth Placental abruption with adverse outcome Eclampsia Uterine rupture Primary postpartum haemorrhage requiring additional treatment or blood transfusion Retained placenta requiring manual removal in theatre Caesarean section Shoulder dystocia Current pregnancy Multiple birth Placenta praevia Pre‑eclampsia or pregnancy‑induced hypertension Preterm labour or preterm prelabour rupture of membranes Placental abruption Anaemia – haemoglobin less than 85 g/litre at onset of labour Confirmed intrauterine death Induction of labour Substance misuse Alcohol dependency requiring assessment or treatment Onset of gestational diabetes Malpresentation – breech or transverse lie BMI at booking of greater than 35 kg/m2 Recurrent antepartum haemorrhage Small for gestational age in this pregnancy (less than fifth centile or reduced growth velocity on ultrasound) Abnormal fetal heart rate/doppler studies Ultrasound diagnosis of oligo‑/polyhydramnios Previous gynaecological history Myomectomy Hysterotomy Disease area Medical condition Cardiovascular Cardiac disease without intrapartum implications Haematological Atypical antibodies not putting the baby at risk of haemolytic disease Sickle‑cell trait Thalassaemia trait Anaemia – haemoglobin 85 to 105 g/litre at onset of labour Infective Hepatitis B/C with normal liver function tests Immune Non‑specific connective tissue disorders Endocrine Unstable hypothyroidism such that a change in treatment is required Skeletal/neurological Spinal abnormalities Previous fractured pelvis Neurological deficits Gastrointestinal Liver disease without current abnormal liver function Crohn's disease Ulcerative colitis Factor Additional information Previous complications Stillbirth/neonatal death with a known non‑recurrent cause Pre‑eclampsia developing at term Placental abruption with good outcome History of previous baby more than 4.5 kg Extensive vaginal, cervical, or third‑ or fourth‑degree perineal trauma Previous term baby with jaundice requiring exchange transfusion Current pregnancy Antepartum bleeding of unknown origin (single episode after 24 weeks of gestation) BMI at booking of 30 to 35 kg/m2 Blood pressure of 140 mmHg systolic or 90 mmHg diastolic or more on 2 occasions Clinical or ultrasound suspicion of macrosomia Para 4 or more Recreational drug use Under current outpatient psychiatric care Age over 35 at booking Fetal indications Fetal abnormality Previous gynaecological history Major gynaecological surgery Cone biopsy or large loop excision of the transformation zone Fibroids ## Women's experience in all birth settings For all women giving birth in all birth settings, follow the principles in the NICE guideline on patient experience in adult NHS services. Providers, senior staff and all healthcare professionals should ensure that in all birth settings there is a culture of respect for each woman as an individual undergoing a significant and emotionally intense life experience, so that the woman is in control, is listened to and is cared for with compassion, and that appropriate informed consent is sought. Senior staff should demonstrate, through their own words and behaviour, appropriate ways of relating to and talking about women and their birth companion(s), and of talking about birth and the choices to be made when giving birth. ## One‑to‑one care in all birth settings Maternity services should: provide a model of care that supports one‑to‑one care in labour for all women and benchmark services and identify overstaffing or understaffing by using workforce planning models and/or woman‑to‑midwife ratios. ## Service organisation and clinical governance Ensure that all women giving birth have timely access to an obstetric unit if they need transfer of care for medical reasons or because they request regional analgesia. Commissioners and providers (this can also include networks of providers) should ensure that there are: robust protocols in place for transfer of care between settings (see also the section on general principles for transfer of care) clear local pathways for the continued care of women who are transferred from one setting to another, including: when crossing provider boundaries if the nearest obstetric or neonatal unit is closed to admissions or the local midwifery‑led unit is full. Commissioners and providers (this can also include networks of providers) should ensure that there are multidisciplinary clinical governance structures in place to enable the oversight of all birth settings. These structures should include, as a minimum, midwifery (including a supervisor of midwives), obstetric, anaesthetic and neonatal expertise, and adequately supported user representation. # Care throughout labour ## Communication Treat all women in labour with respect. Ensure that the woman is in control of and involved in what is happening to her, and recognise that the way in which care is given is key to this. To facilitate this, establish a rapport with the woman, ask her about her wants and expectations for labour, and be aware of the importance of tone and demeanour, and of the actual words used. Use this information to support and guide her through her labour. To establish communication with the woman: Greet the woman with a smile and a personal welcome, establish her language needs, introduce yourself and explain your role in her care. Maintain a calm and confident approach so that your demeanour reassures the woman that all is going well. Knock and wait before entering the woman's room, respecting it as her personal space, and ask others to do the same. Ask how the woman is feeling and whether there is anything in particular she is worried about. If the woman has a written birth plan, read and discuss it with her. Assess the woman's knowledge of strategies for coping with pain and provide balanced information to find out which available approaches are acceptable to her. Encourage the woman to adapt the environment to meet her individual needs. Ask her permission before all procedures and observations, focusing on the woman rather than the technology or the documentation. Show the woman and her birth companion(s) how to summon help and reassure her that she may do so whenever and as often as she needs to. When leaving the room, let her know when you will return. Involve the woman in any handover of care to another professional, either when additional expertise has been brought in or at the end of a shift. ## Mobilisation Encourage and help the woman to move and adopt whatever positions she finds most comfortable throughout labour. ## Support Encourage the woman to have support from birth companion(s) of her choice. ## Hygiene measures Tap water may be used if cleansing is required before vaginal examination. Routine hygiene measures taken by staff caring for women in labour, including standard hand hygiene and single‑use non‑sterile gloves, are appropriate to reduce cross‑contamination between women, babies and healthcare professionals. Selection of protective equipment must be based on an assessment of the risk of transmission of microorganisms to the woman, and the risk of contamination of the healthcare worker's clothing and skin by women's blood, body fluids, secretions or excretions. This is in accordance with the following health and safety legislation (current at the time NICE's guideline on healthcare-associated infections was published ): Health and Safety at Work Act 1974, Management of Health and Safety at Work Regulations 1999, Health and Safety Regulations 2002, Control of Substances Hazardous to Health Regulations 2002, Personal Protective Equipment Regulations 2002 and Health and Social Care Act 2008). This recommendation is adapted from NICE's guideline on healthcare-associated infections. # Latent first stage of labour ## Definitions of the latent and established first stages of labour For the purposes of this guideline, use the following definitions of labour: Latent first stage of labour – a period of time, not necessarily continuous, when: there are painful contractions and there is some cervical change, including cervical effacement and dilatation up to 4 cm. Established first stage of labour – when: there are regular painful contractions and there is progressive cervical dilatation from 4 cm. ## Education and early assessment Give all nulliparous women information antenatally about: what to expect in the latent first stage of labour how to work with any pain they experience how to contact their midwifery care team and what to do in an emergency. Offer all nulliparous women antenatal education about the signs of labour, consisting of: how to differentiate between Braxton Hicks contractions and active labour contractions the expected frequency of contractions and how long they last recognition of amniotic fluid ('waters breaking') description of normal vaginal loss. Consider an early assessment of labour by telephone triage provided by a dedicated triage midwife for all women. Consider a face‑to‑face early assessment of labour for all low‑risk nulliparous women, either: at home (regardless of planned place of birth) or in an assessment facility in her planned place of birth (midwifery‑led unit or obstetric unit), comprising one‑to‑one midwifery care for at least 1 hour. Include the following in any early or triage assessment of labour: ask the woman how she is, and about her wishes, expectations and any concerns she has ask the woman about the baby's movements, including any changes give information about what the woman can expect in the latent first stage of labour and how to work with any pain she experiences give information about what to expect when she accesses care agree a plan of care with the woman, including guidance about who she should contact next and when provide guidance and support to the woman's birth companion(s). The triage midwife should document the guidance that she gives to the woman. If a woman seeks advice or attends a midwifery‑led unit or obstetric unit with painful contractions, but is not in established labour: recognise that a woman may experience painful contractions without cervical change, and although she is described as not being in labour, she may well think of herself as being 'in labour' by her own definition -ffer her individualised support, and analgesia if needed encourage her to remain at or return home, unless doing so leads to a significant risk that she could give birth without a midwife present or become distressed. ## Pain relief Advise the woman and her birth companion(s) that breathing exercises, immersion in water and massage may reduce pain during the latent first stage of labour. (See also the recommendation on timing of regional analgesia.) Do not offer or advise aromatherapy, yoga or acupressure for pain relief during the latent first stage of labour. If a woman wants to use any of these techniques, respect her wishes. # Initial assessment When performing an initial assessment of a woman in labour, listen to her story and take into account her preferences and her emotional and psychological needs. Carry out an initial assessment to determine if midwifery‑led care in any setting is suitable for the woman, irrespective of any previous plan. The assessment should comprise the following: Observations of the woman: Review the antenatal notes (including all antenatal screening results) and discuss these with the woman. Ask her about the length, strength and frequency of her contractions. Ask her about any pain she is experiencing and discuss her options for pain relief. Record her pulse, blood pressure and temperature, and carry out urinalysis. Record if she has had any vaginal loss. Observations of the unborn baby: Ask the woman about the baby's movements in the last 24 hours. Palpate the woman's abdomen to determine the fundal height, the baby's lie, presentation, position, engagement of the presenting part, and frequency and duration of contractions. Auscultate the fetal heart rate for a minimum of 1 minute immediately after a contraction. Palpate the woman's pulse to differentiate between the heartbeats of the woman and the baby.In addition (see also recommendation 1.4.5): If there is uncertainty about whether the woman is in established labour, a vaginal examination may be helpful after a period of assessment, but is not always necessary. If the woman appears to be in established labour, offer a vaginal examination. Transfer the woman to obstetric‑led care, following the section on the general principles for transfer of care, if any of the following are observed on initial assessment: Observations of the woman: pulse over 120 beats/minute on 2 occasions 30 minutes apart a single reading of either raised diastolic blood pressure of 110 mmHg or more or raised systolic blood pressure of 160 mmHg or more either raised diastolic blood pressure of 90 mmHg or more or raised systolic blood pressure of 140 mmHg or more on 2 consecutive readings taken 30 minutes apart a reading of 2+ of protein on urinalysis and a single reading of either raised diastolic blood pressure (90 mmHg or more) or raised systolic blood pressure (140 mmHg or more) temperature of 38°C or above on a single reading, or 37.5°C or above on 2 consecutive readings 1 hour apart any vaginal blood loss other than a show rupture of membranes more than 24 hours before the onset of established labour (see the section on babies born to women with prelabour rupture of the membranes at term) the presence of significant meconium (see the section on presence of meconium) pain reported by the woman that differs from the pain normally associated with contractions any risk factors recorded in the woman's notes that indicate the need for obstetric led care. Observations of the unborn baby: any abnormal presentation, including cord presentation transverse or oblique lie high (4/5 to 5/5 palpable) or free‑floating head in a nulliparous woman suspected fetal growth restriction or macrosomia suspected anhydramnios or polyhydramnios fetal heart rate below 110 or above 160 beats/minute a deceleration in fetal heart rate heard on intermittent auscultation reduced fetal movements in the last 24 hours reported by the woman.If none of these are observed, continue with midwifery-led care unless the woman requests transfer (see also the section on measuring fetal heart rate as part of initial assessment). If any of the factors in recommendation 1.4.3 are observed but birth is imminent, assess whether birth in the current location is preferable to transferring the woman to an obstetric unit and discuss this with the coordinating midwife. When conducting a vaginal examination: be sure that the examination is necessary and will add important information to the decision‑making process recognise that a vaginal examination can be very distressing for a woman, especially if she is already in pain, highly anxious and in an unfamiliar environment explain the reason for the examination and what will be involved ensure the woman's informed consent, privacy, dignity and comfort explain sensitively the findings of the examination and any impact on the birth plan to the woman and her birth companion(s). ## Measuring fetal heart rate as part of initial assessment Offer auscultation of the fetal heart rate at first contact with a woman in suspected or established labour, and at each further assessment: Use either a Pinard stethoscope or doppler ultrasound. Carry out auscultation immediately after a contraction for at least 1 minute and record it as a single rate. Record accelerations and decelerations if heard. Palpate the maternal pulse to differentiate between the maternal and fetal heartbeats. Be aware that for women at low risk of complications there is insufficient evidence about whether cardiotocography as part of the initial assessment either improves outcomes or results in harm for women and their babies, compared with intermittent auscultation alone. If a woman at low risk of complications requests cardiotocography as part of the initial assessment: discuss the risks, benefits and limitations of cardiotocography with her, and support her in her choice explain that, if she is in a setting where cardiotocography is not available, she will need to be transferred to obstetric-led care. Offer continuous cardiotocography if any of the risk factors listed in recommendation 1.4.3 in the section on initial assessment are identified on initial assessment, and explain to the woman why this is being offered. (See also the NICE guideline on fetal monitoring in labour for further guidance on fetal monitoring.) Offer cardiotocography if intermittent auscultation indicates possible fetal heart rate abnormalities, and explain to the woman why this is being offered. If the trace is normal (see the section on the use of cardiotocography for monitoring during labour in the NICE guideline on fetal monitoring in labour) after 20 minutes, return to intermittent auscultation unless the woman asks to stay on continuous cardiotocography. If fetal death is suspected despite the presence of an apparently recorded fetal heart rate, offer real-time ultrasound assessment to check fetal viability. # Ongoing assessment Transfer the woman to obstetric‑led care (following the general principles for transfer of care) if any of the following are observed at any point, unless the risks of transfer outweigh the benefits: Observations of the woman: pulse over 120 beats/minute on 2 occasions 30 minutes apart a single reading of either raised diastolic blood pressure of 110 mmHg or more or raised systolic blood pressure of 160 mmHg or more either raised diastolic blood pressure of 90 mmHg or more or raised systolic blood pressure of 140 mmHg or more on 2 consecutive readings taken 30 minutes apart a reading of 2+ of protein on urinalysis and a single reading of either raised diastolic blood pressure (90 mmHg or more) or raised systolic blood pressure (140 mmHg or more) temperature of 38°C or above on a single reading, or 37.5°C or above on 2 consecutive occasions 1 hour apart any vaginal blood loss other than a show the presence of significant meconium (see the section on presence of meconium) pain reported by the woman that differs from the pain normally associated with contractions confirmed delay in the first or second stage of labour request by the woman for additional pain relief using regional analgesia -bstetric emergency – including antepartum haemorrhage, cord prolapse, postpartum haemorrhage, maternal seizure or collapse, or a need for advanced neonatal resuscitation retained placenta third‑degree or fourth‑degree tear or other complicated perineal trauma that needs suturing. Observations of the unborn baby: any abnormal presentation, including cord presentation transverse or oblique lie high (4/5 to 5/5 palpable) or free‑floating head in a nulliparous woman suspected fetal growth restriction or macrosomia suspected anhydramnios or polyhydramnios fetal heart rate below 110 or above 160 beats/minute a deceleration in fetal heart rate heard on intermittent auscultation.If none of these are observed, continue with midwifery-led care unless the woman requests transfer (see also recommendation 1.4.6 in the section on measuring fetal heart rate as part of initial assessment). ## Presence of meconium As part of ongoing assessment, document the presence or absence of significant meconium. This is defined as dark green or black amniotic fluid that is thick or tenacious, or any meconium‑stained amniotic fluid containing lumps of meconium. If significant meconium is present, ensure that: healthcare professionals trained in fetal blood sampling are available during labour and healthcare professionals trained in advanced neonatal life support are readily available for the birth. If significant meconium is present, transfer the woman to obstetric‑led care provided that it is safe to do so and the birth is unlikely to occur before transfer is completed. Follow the general principles for transfer of care described in section 1.6. # General principles for transfer of care Transfer of care refers to the transfer between midwifery‑led care and obstetric‑led care. This may or may not involve transport from one location to another. Women who are receiving midwifery‑led care in an obstetric unit can have their care transferred to obstetric‑led care without being moved. Base any decisions about transfer of care on clinical findings, and discuss the options with the woman and her birth companion(s). If contemplating transfer of care: talk with the woman and her birth companion(s) about the reasons for this and what they can expect, including the time needed for transfer address any concerns she has and try to allay her anxiety ensure that her wishes are respected and her informed consent is obtained. When arranging transfer of care, the midwife attending the labour should contact the ambulance service (if appropriate) and the coordinating midwife in the obstetric unit. The coordinating midwife should then alert the relevant healthcare professionals (obstetric, anaesthetic and neonatal). When arranging transfer from one location to another, ensure the following: Before transfer, the woman is dressed, wrapped in a blanket or otherwise covered in a way that she feels is comfortable and appropriate. The woman is made to feel as comfortable as possible before and during transfer. Any ambulance staff or other personnel involved are aware that some positions may make the woman uncomfortable or afraid and could affect her labour, so she should be encouraged to choose how to move and what position to adopt if possible, in accordance with ambulance service protocols. Communication and companionship are maintained. Explain the arrangements for transfer to the woman and her birth companion(s). A midwife who has been involved in her care up to that point should travel with her and carry out a handover of care that involves the woman. Arrangements are in place to enable the woman's birth companion(s) to travel with her in the ambulance if that is what she wants. If this is not possible or not wanted, check that the birth companion(s) have or can arrange their own transport. If a woman is transferred to an obstetric unit after the birth (see the section on care of the woman after birth), ensure that her baby goes with her. # Care in established labour ## Support in labour Provide a woman in established labour with supportive one‑to‑one care. Do not leave a woman in established labour on her own except for short periods or at the woman's request. For guidance on ensuring continuity of care, see recommendation 1.4.1 in the NICE guideline on patient experience in adult NHS services. ## Controlling gastric acidity Do not offer either H2‑receptor antagonists or antacids routinely to low‑risk women. Either H2‑receptor antagonists or antacids should be considered for women who receive opioids or who have or develop risk factors that make a general anaesthetic more likely. Inform the woman that she may drink during established labour and that isotonic drinks may be more beneficial than water. Inform the woman that she may eat a light diet in established labour unless she has received opioids or she develops risk factors that make a general anaesthetic more likely. # Pain relief in labour: non‑regional ## Attitudes to pain and pain relief in childbirth Healthcare professionals should think about how their own values and beliefs inform their attitude to coping with pain in labour and ensure their care supports the woman's choice. ## Pain‑relieving strategies If a woman chooses to use breathing and relaxation techniques in labour, support her in this choice. If a woman chooses to use massage techniques in labour that have been taught to birth companions, support her in this choice. Offer the woman the opportunity to labour in water for pain relief. For women labouring in water, monitor the temperature of the woman and the water hourly to ensure that the woman is comfortable and not becoming pyrexial. The temperature of the water should not be above 37.5°C. Keep baths and birthing pools clean using a protocol agreed with the microbiology department and, in the case of birthing pools, in accordance with the manufacturer's guidelines. Do not use injected water papules. Do not offer acupuncture, acupressure or hypnosis, but do not prevent women who wish to use these techniques from doing so. Support the playing of music of the woman's choice in labour. ## Non‑pharmacological analgesia Do not offer transcutaneous electrical nerve stimulation (TENS) to women in established labour. ## Inhalational analgesia Ensure that Entonox (a 50:50 mixture of oxygen and nitrous oxide) is available in all birth settings as it may reduce pain in labour, but inform the woman that it may make her feel nauseous and light‑headed. ## Intravenous and intramuscular opioids Ensure that pethidine, diamorphine or other opioids are available in all birth settings. Inform the woman that these will provide limited pain relief during labour and may have significant side effects for both her (drowsiness, nausea and vomiting) and her baby (short‑term respiratory depression and drowsiness which may last several days). Inform the woman that pethidine, diamorphine or other opioids may interfere with breastfeeding. If an intravenous or intramuscular opioid is used, also administer an antiemetic. Women should not enter water (a birthing pool or bath) within 2 hours of opioid administration or if they feel drowsy. # Pain relief in labour: regional analgesia ## Information about regional analgesia If a woman is contemplating regional analgesia, talk with her about the risks and benefits and the implications for her labour, including the arrangements and time involved for transfer of care to an obstetric unit if she is at home or in a midwifery unit (follow the general principles for transfer of care). Provide information about epidural analgesia, including the following: It is available only in obstetric units. It provides more effective pain relief than opioids. It is not associated with long‑term backache. It is not associated with a longer first stage of labour or an increased chance of a caesarean birth. It is associated with a longer second stage of labour and an increased chance of vaginal instrumental birth. It will be accompanied by a more intensive level of monitoring and intravenous access, and so mobility may be reduced. ## Timing of regional analgesia If a woman in labour asks for regional analgesia, comply with her request. This includes women in severe pain in the latent first stage of labour. ## Care and observations for women with regional analgesia Always secure intravenous access before starting regional analgesia. Preloading and maintenance fluid infusion need not be administered routinely before establishing low‑dose epidural analgesia and combined spinal–epidural analgesia. Undertake the following additional observations for women with regional analgesia: During establishment of regional analgesia or after further boluses (10 ml or more of low‑dose solutions), measure blood pressure every 5 minutes for 15 minutes. If the woman is not pain‑free 30 minutes after each administration of local anaesthetic/opioid solution, recall the anaesthetist. Assess the level of the sensory block hourly. Encourage women with regional analgesia to move and adopt whatever upright positions they find comfortable throughout labour. Once established, continue regional analgesia until after completion of the third stage of labour and any necessary perineal repair. Upon confirmation of full cervical dilatation in a woman with regional analgesia, unless the woman has an urge to push or the baby's head is visible, pushing should be delayed for at least 1 hour and longer if the woman wishes, after which actively encourage her to push during contractions. After diagnosis of full dilatation in a woman with regional analgesia, agree a plan with the woman in order to ensure that birth will have occurred within 4 hours regardless of parity. Do not routinely use oxytocin in the second stage of labour for women with regional analgesia. Perform continuous cardiotocography for at least 30 minutes during establishment of regional analgesia and after administration of each further bolus of 10 ml or more. ## Establishing and maintaining regional analgesia Use either epidural or combined spinal–epidural analgesia for establishing regional analgesia in labour. If rapid analgesia is required, use combined spinal–epidural analgesia. Establish combined spinal–epidural analgesia with bupivacaine and fentanyl. Establish epidural analgesia with a low‑concentration local anaesthetic and opioid solution with, for example, 10 to 15 ml of 0.0625 to 0.1% bupivacaine with 1 to 2 micrograms per ml fentanyl. The initial dose of local anaesthetic plus opioid is essentially a test dose, so administer cautiously to ensure that inadvertent intrathecal injection has not occurred. Use low‑concentration local anaesthetic and opioid solutions (0.0625 to 0.1% bupivacaine or equivalent combined with 2.0 micrograms per ml fentanyl) for maintaining epidural analgesia in labour. Do not use high concentrations of local anaesthetic solutions (0.25% or above of bupivacaine or equivalent) routinely for either establishing or maintaining epidural analgesia. Either patient‑controlled epidural analgesia or intermittent bolus given by healthcare professionals are the preferred modes of administration for maintenance of epidural analgesia. # Monitoring during labour The recommendations in this section have been withdrawn. For advice on monitoring during labour, see the NICE guideline on fetal monitoring in labour. # Prelabour rupture of membranes at term Do not carry out a speculum examination if it is certain that the membranes have ruptured. If it is uncertain whether prelabour rupture of the membranes has occurred, offer the woman a speculum examination to determine whether the membranes have ruptured. Avoid digital vaginal examination in the absence of contractions. Advise women presenting with prelabour rupture of the membranes at term that: the risk of serious neonatal infection is 1%, rather than 0.5% for women with intact membranes % of women with prelabour rupture of the membranes will go into labour within 24 hours induction of labour (see NICE's guideline on inducing labour) is appropriate approximately 24 hours after rupture of the membranes. Until the induction is started or if expectant management beyond 24 hours is chosen by the woman: do not offer lower vaginal swabs and measurement of maternal C‑reactive protein to detect any infection that may be developing, advise the woman to record her temperature every 4 hours during waking hours and to report immediately any change in the colour or smell of her vaginal loss inform the woman that bathing or showering is not associated with an increase in infection, but that having sexual intercourse may be. Assess fetal movement and heart rate at initial contact and then every 24 hours after rupture of the membranes while the woman is not in labour, and advise the woman to report immediately any decrease in fetal movements. If labour has not started 24 hours after rupture of the membranes, advise the woman to give birth where there is access to neonatal services and to stay in hospital for at least 12 hours after the birth. # First stage of labour See the recommendation on definitions of the latent and established first stages of labour. Do not offer or advise clinical intervention if labour is progressing normally and the woman and baby are well. In all stages of labour, women who have left the normal care pathway because of the development of complications can return to it if/when the complication is resolved. ## Duration of the first stage Inform women that, while the length of established first stage of labour varies between women: first labours last on average 8 hours and are unlikely to last over 18 hours second and subsequent labours last on average 5 hours and are unlikely to last over 12 hours. ## Observations during the established first stage Do not routinely use verbal assessment using a numerical pain score. Use a pictorial record of labour (partogram) once labour is established. Where the partogram includes an action line, use the World Health Organization (WHO) recommendation of a 4‑hour action line (the WHO partograph in management of labour, published in 1994 as part of the Maternal Health and Safe Motherhood Programme. Lancet 343: 1399 to 404). See also the WHO Multicountry Survey on Maternal and Newborn Health. Record the following observations during the first stage of labour: half‑hourly documentation of frequency of contractions hourly pulse ‑hourly temperature and blood pressure frequency of passing urine -ffer a vaginal examination (see recommendation 1.4.5 in the section on initial assessment) 4‑hourly or if there is concern about progress or in response to the woman's wishes (after abdominal palpation and assessment of vaginal loss). If any of the indications for transfer are met (see the recommendation on ongoing assessment), transfer the woman to obstetric‑led care. Follow the general principles for transfer of care. Give ongoing consideration to the woman's emotional and psychological needs, including her desire for pain relief. Encourage the woman to communicate her need for analgesia at any point during labour. ## Possible routine interventions in the first stage Do not routinely offer the package known as active management of labour (one‑to‑one continuous support; strict definition of established labour; early routine amniotomy; routine 2‑hourly vaginal examination; oxytocin if labour becomes slow). In normally progressing labour, do not perform amniotomy routinely. Do not use combined early amniotomy with use of oxytocin routinely. ## Delay in the first stage If delay in the established first stage is suspected, take the following into account: parity cervical dilatation and rate of change uterine contractions station and position of presenting part the woman's emotional state referral to the appropriate healthcare professional.Offer the woman support, hydration, and appropriate and effective pain relief. If delay in the established first stage is suspected, assess all aspects of progress in labour when diagnosing delay, including: cervical dilatation of less than 2 cm in 4 hours for first labours cervical dilatation of less than 2 cm in 4 hours or a slowing in the progress of labour for second or subsequent labours descent and rotation of the baby's head changes in the strength, duration and frequency of uterine contractions. If delay is diagnosed, transfer the woman to obstetric‑led care. Follow the general principles for transfer of care. If delay in the established first stage of labour is suspected, amniotomy should be considered for all women with intact membranes, after explanation of the procedure and advice that it will shorten her labour by about an hour and may increase the strength and pain of her contractions. Whether or not a woman has agreed to an amniotomy, advise all women with suspected delay in the established first stage of labour to have a vaginal examination 2 hours later, and diagnose delay if progress is less than 1 cm. For women with intact membranes in whom delay in the established first stage of labour is confirmed, advise the woman to have an amniotomy, and to have a repeat vaginal examination 2 hours later whether her membranes are ruptured or intact. For all women with confirmed delay in the established first stage of labour: transfer the woman to obstetric‑led care for an obstetric review and a decision about management options, including the use of oxytocin (follow the general principles for transfer of care) explain to her that using oxytocin after spontaneous or artificial rupture of the membranes will bring forward the time of birth but will not influence the mode of birth or other outcomes. For a multiparous woman with confirmed delay in the established first stage of labour, an obstetrician should perform a full assessment, including abdominal palpation and vaginal examination, before a decision is made about using oxytocin. Offer all women with delay in the established first stage of labour support and effective pain relief. Inform the woman that oxytocin will increase the frequency and strength of her contractions and that its use will mean that her baby should be monitored continuously. Offer the woman an epidural before oxytocin is started. If oxytocin is used, ensure that the time between increments of the dose is no more frequent than every 30 minutes. Increase oxytocin until there are 4 to 5 contractions in 10 minutes. (See also recommendation 1.12.14 and recommendation 1.3.8 in the NICE guideline on fetal monitoring in labour.) Advise the woman to have a vaginal examination 4 hours after starting oxytocin in established labour: If cervical dilatation has increased by less than 2 cm after 4 hours of oxytocin, further obstetric review is required to assess the need for caesarean section. If cervical dilatation has increased by 2 cm or more, advise 4‑hourly vaginal examinations. # Second stage of labour ## Definition of the second stage For the purposes of this guideline, use the following definitions of labour: Passive second stage of labour: the finding of full dilatation of the cervix before or in the absence of involuntary expulsive contractions. Onset of the active second stage of labour: the baby is visible expulsive contractions with a finding of full dilatation of the cervix or other signs of full dilatation of the cervix active maternal effort following confirmation of full dilatation of the cervix in the absence of expulsive contractions. ## Observations during the second stage Carry out the following observations in the second stage of labour, record all observations on the partogram and assess whether transfer of care may be needed (see the recommendation on ongoing assessment). : half‑hourly documentation of the frequency of contractions hourly blood pressure continued 4‑hourly temperature frequency of passing urine -ffer a vaginal examination (see recommendation 1.4.5 in the section on initial assessment) hourly in the active second stage, or in response to the woman's wishes (after abdominal palpation and assessment of vaginal loss). In addition: Continue to take the woman's emotional and psychological needs into account. Assess progress, which should include the woman's behaviour, the effectiveness of pushing and the baby's wellbeing, taking into account the baby's position and station at the onset of the second stage. These factors will assist in deciding the timing of further vaginal examination and any need for transfer to obstetric led care. Perform intermittent auscultation of the fetal heart rate immediately after a contraction for at least 1 minute, at least every 5 minutes. Palpate the woman's pulse every 15 minutes to differentiate between the two heartbeats. Ongoing consideration should be given to the woman's position, hydration, coping strategies and pain relief throughout the second stage. ## Duration of the second stage and definition of delay For a nulliparous woman: birth would be expected to take place within 3 hours of the start of the active second stage in most women diagnose delay in the active second stage when it has lasted 2 hours and refer the woman to a healthcare professional trained to undertake an operative vaginal birth if birth is not imminent. For a multiparous woman: birth would be expected to take place within 2 hours of the start of the active second stage in most women diagnose delay in the active second stage when it has lasted 1 hour and refer the woman to a healthcare professional trained to undertake an operative vaginal birth if birth is not imminent. For a nulliparous woman, suspect delay if progress (in terms of rotation and/or descent of the presenting part) is inadequate after 1 hour of active second stage. Offer vaginal examination and then offer amniotomy if the membranes are intact. For a multiparous woman, suspect delay if progress (in terms of rotation and/or descent of the presenting part) is inadequate after 30 minutes of active second stage. Offer vaginal examination and then offer amniotomy if the membranes are intact. If full dilatation of the cervix has been confirmed in a woman without regional analgesia, but she does not get an urge to push, carry out further assessment after 1 hour. ## Oxytocin in the second stage Consideration should be given to the use of oxytocin, with the offer of regional analgesia, for nulliparous women if contractions are inadequate at the onset of the second stage. ## The woman's position and pushing in the second stage Discourage the woman from lying supine or semi‑supine in the second stage of labour and encourage her to adopt any other position that she finds most comfortable. Inform the woman that in the second stage she should be guided by her own urge to push. If pushing is ineffective or if requested by the woman, offer strategies to assist birth, such as support, change of position, emptying of the bladder and encouragement. ## Intrapartum interventions to reduce perineal trauma Do not perform perineal massage in the second stage of labour. Either the 'hands on' (guarding the perineum and flexing the baby's head) or the 'hands poised' (with hands off the perineum and baby's head but in readiness) technique can be used to facilitate spontaneous birth. Do not offer lidocaine spray to reduce pain in the second stage of labour. Do not carry out a routine episiotomy during spontaneous vaginal birth. Inform any woman with a history of severe perineal trauma that her risk of repeat severe perineal trauma is not increased in a subsequent birth, compared with women having their first baby. Do not offer episiotomy routinely at vaginal birth after previous third‑ or fourth‑degree trauma. In order for a woman who has had previous third- or fourth‑degree trauma to make an informed choice, talk with her about the future mode of birth, encompassing: current urgency or incontinence symptoms the degree of previous trauma risk of recurrence the success of the repair undertaken the psychological effect of the previous trauma management of her labour. Inform any woman with infibulated genital mutilation of the risks of difficulty with vaginal examination, catheterisation and application of fetal scalp electrodes. Inform her of the risks of delay in the second stage and spontaneous laceration together with the need for an anterior episiotomy and the possible need for defibulation in labour. If an episiotomy is performed, the recommended technique is a mediolateral episiotomy originating at the vaginal fourchette and usually directed to the right side. The angle to the vertical axis should be between 45 and 60 degrees at the time of the episiotomy. Perform an episiotomy if there is a clinical need, such as instrumental birth or suspected fetal compromise. Provide tested effective analgesia before carrying out an episiotomy, except in an emergency because of acute fetal compromise. ## Water birth Inform women that there is insufficient high‑quality evidence to either support or discourage giving birth in water. ## Delay in the second stage If there is delay in the second stage of labour, or if the woman is excessively distressed, support and sensitive encouragement and the woman's need for analgesia/anaesthesia are particularly important. An obstetrician should assess a woman with confirmed delay in the second stage (after transfer to obstetric‑led care, following the general principles for transfer of care) before contemplating the use of oxytocin. After initial obstetric assessment of a woman with delay in the second stage, maintain ongoing obstetric review every 15 to 30 minutes. ## Instrumental birth and delayed second stage Think about offering instrumental birth if there is concern about the baby's wellbeing or there is a prolonged second stage. Recognise that, on rare occasions, the woman's need for help in the second stage may be an indication to assist by offering instrumental birth when supportive care has not helped. The choice of instrument depends on a balance of clinical circumstance and practitioner experience. Because instrumental birth is an operative procedure, advise the woman to have tested effective anaesthesia. If a woman declines anaesthesia, offer a pudendal block combined with local anaesthetic to the perineum during instrumental birth. If there is concern about fetal compromise, offer either tested effective anaesthesia or, if time does not allow this, a pudendal block combined with local anaesthetic to the perineum during instrumental birth. Advise the woman to have a caesarean section if vaginal birth is not possible (see the NICE guideline on caesarean birth). . ## Expediting birth If the birth needs to be expedited for maternal or fetal reasons, assess both the risk to the baby and the safety of the woman. Assessments should include: the degree of urgency clinical findings on abdominal and vaginal examination choice of mode of birth (and whether to use forceps or ventouse if an instrumental birth is indicated) anticipated degree of difficulty, including the likelihood of success if instrumental birth is attempted location any time that may be needed for transfer to obstetric‑led care the need for additional analgesia or anaesthesia the woman's preferences. Talk with the woman and her birth companion(s) about why the birth needs to be expedited and what the options are. Inform the team about the degree of urgency. Record the time at which the decision to expedite the birth is made. # Third stage of labour Recognise that the time immediately after the birth is when the woman and her birth companion(s) are meeting and getting to know the baby. Ensure that any care or interventions are sensitive to this and minimise separation or disruption of the mother and baby. ## Definition of the third stage For the purposes of this guideline, use the following definitions: The third stage of labour is the time from the birth of the baby to the expulsion of the placenta and membranes. Active management of the third stage involves a package of care comprising the following components: routine use of uterotonic drugs deferred clamping and cutting of the cord controlled cord traction after signs of separation of the placenta. Physiological management of the third stage involves a package of care that includes the following components: no routine use of uterotonic drugs no clamping of the cord until pulsation has stopped delivery of the placenta by maternal effort. ## Prolonged third stage Diagnose a prolonged third stage of labour if it is not completed within 30 minutes of the birth with active management or within 60 minutes of the birth with physiological management. Follow the recommendations on managing retained placenta. ## Observations in the third stage Record the following observations for a woman in the third stage of labour: her general physical condition, as shown by her colour, respiration and her own report of how she feels vaginal blood loss. If there is postpartum haemorrhage, a retained placenta or maternal collapse, or any other concerns about the woman's wellbeing: transfer her to obstetric‑led care (following the general principles for transfer of care) carry out frequent observations to assess whether resuscitation is needed. ## Active and physiological management of the third stage Explain to the woman antenatally about what to expect with each package of care for managing the third stage of labour and the benefits and risks associated with each. Explain to the woman that active management: shortens the third stage compared with physiological management is associated with nausea and vomiting in about 100 in 1,000 women is associated with an approximate risk of 13 in 1,000 of a haemorrhage of more than 1 litre is associated with an approximate risk of 14 in 1,000 of a blood transfusion. Explain to the woman that physiological management: is associated with nausea and vomiting in about 50 in 1,000 women is associated with an approximate risk of 29 in 1,000 of a haemorrhage of more than 1 litre is associated with an approximate risk of 40 in 1,000 of a blood transfusion. Discuss again with the woman at the initial assessment in labour (see the section on initial assessment) about the different options for managing the third stage and ways of supporting her during delivery of the placenta, and ask if she has any preferences. Advise the woman to have active management of the third stage, because it is associated with a lower risk of a postpartum haemorrhage and/or blood transfusion. If a woman at low risk of postpartum haemorrhage requests physiological management of the third stage, support her in her choice. Document in the records the decision that is agreed with the woman about management of the third stage. For active management, administer 10 IU of oxytocin by intramuscular injection with the birth of the anterior shoulder or immediately after the birth of the baby and before the cord is clamped and cut. Use oxytocin as it is associated with fewer side effects than oxytocin plus ergometrine. After administering oxytocin, clamp and cut the cord. Do not clamp the cord earlier than 1 minute from the birth of the baby unless there is concern about the integrity of the cord or the baby has a heart rate below 60 beats/minute that is not getting faster. Clamp the cord before 5 minutes in order to perform controlled cord traction as part of active management. If the woman requests that the cord is clamped and cut later than 5 minutes, support her in her choice. After cutting the cord, use controlled cord traction. Perform controlled cord traction as part of active management only after administration of oxytocin and signs of separation of the placenta. Record the timing of cord clamping in both active and physiological management. Advise a change from physiological management to active management if either of the following occur: haemorrhage the placenta is not delivered within 1 hour of the birth of the baby. Offer a change from physiological management to active management if the woman wants to shorten the third stage. Do not use either umbilical oxytocin infusion or prostaglandin routinely in the third stage of labour. ## Retained placenta Secure intravenous access if the placenta is retained, and explain to the woman why this is needed. Do not use umbilical vein agents if the placenta is retained. Do not use intravenous oxytocic agents routinely to deliver a retained placenta. Give intravenous oxytocic agents if the placenta is retained and the woman is bleeding excessively. If the placenta is retained and there is concern about the woman's condition: -ffer a vaginal examination to assess the need to undertake manual removal of the placenta explain that this assessment can be painful and advise her to have analgesia. If the woman reports inadequate analgesia during the assessment, stop the examination and address this immediately. If uterine exploration is necessary and the woman is not already in an obstetric unit, arrange urgent transfer (following the general principles for transfer of care). Do not carry out uterine exploration or manual removal of the placenta without an anaesthetic. ## Postpartum haemorrhage Advise women with risk factors for postpartum haemorrhage to give birth in an obstetric unit, where more emergency treatment options are available. Antenatal risk factors: previous retained placenta or postpartum haemorrhage maternal haemoglobin level below 85 g/litre at onset of labour BMI greater than 35 kg/m2 grand multiparity (parity 4 or more) antepartum haemorrhage -verdistention of the uterus (for example, multiple pregnancy, polyhydramnios or macrosomia) existing uterine abnormalities low‑lying placenta maternal age of 35 years or older. Risk factors in labour: induction prolonged first, second or third stage of labour -xytocin use precipitate labour -perative birth or caesarean section. If a woman has risk factors for postpartum haemorrhage, highlight these in her notes, and make and discuss with her a care plan covering the third stage of labour. If a woman has a postpartum haemorrhage: call for help give immediate clinical treatment: emptying of the bladder and uterine massage and uterotonic drugs and intravenous fluids and controlled cord traction if the placenta has not yet been delivered continuously assess blood loss and the woman's condition, and identify the source of the bleeding give supplementary oxygen arrange for transfer of the woman to obstetric‑led care (following the general principles for transfer of care). Administer a bolus of one of the following as first‑line treatment for postpartum haemorrhage: -xytocin (10 IU intravenous) or ergometrine (0.5 mg intramuscular) or combined oxytocin and ergometrine (5 IU/0.5 mg intramuscular). Offer second‑line treatment for postpartum haemorrhage if needed. No particular uterotonic drug can be recommended over any other; options include: repeat bolus of: -xytocin (intravenous) ergometrine (intramuscular, or cautiously intravenously) combined oxytocin and ergometrine (intramuscular) misoprostol -xytocin infusion carboprost (intramuscular). Assess the need for adjuvant options for managing significant continuing postpartum haemorrhage, including: tranexamic acid (intravenous) rarely, in the presence of otherwise normal clotting factors, rFactor VIIa, in consultation with a haematologist. Allocate a member of the healthcare team to stay with the woman and her birth companion(s), explain what is happening, answer any questions and offer support throughout the emergency situation. If the haemorrhage continues: perform examination under anaesthetic ensure that the uterus is empty and repair any trauma consider balloon tamponade before surgical options. Be aware that no particular surgical procedure can be recommended over any other for treating postpartum haemorrhage. The maternity service and ambulance service should have strategies in place in order to respond quickly and appropriately if a woman has a postpartum haemorrhage in any setting. # Care of the newborn baby ## Initial assessment of the newborn baby and mother–baby bonding Recommendations 1.15.6, 1.15.8 and 1.15.9 have been adapted from NICE's guideline on postnatal care; refer to this guideline for more information on immediate postnatal care (within 2 hours of birth). Record the Apgar score routinely at 1 and 5 minutes for all births. Record the time from birth to the onset of regular respirations. If the baby is born in poor condition (on the basis of abnormal breathing, heart rate or tone): follow the recommendations in the section on neonatal resuscitation and take paired cord‑blood samples for blood gas analysis, after clamping the cord using 2 clamps.Continue to evaluate and record the baby's condition until it is improved and stable. Do not take paired cord blood samples (for blood gas analysis) routinely. Ensure that a second clamp to allow double‑clamping of the cord is available in all birth settings. Encourage women to have skin‑to‑skin contact with their babies as soon as possible after the birth. In order to keep the baby warm, dry and cover him or her with a warm, dry blanket or towel while maintaining skin‑to‑skin contact with the woman. Avoid separation of a woman and her baby within the first hour of the birth for routine postnatal procedures, for example, weighing, measuring and bathing, unless these measures are requested by the woman, or are necessary for the immediate care of the baby. Encourage initiation of breastfeeding as soon as possible after the birth, ideally within 1 hour. Record head circumference, body temperature and birth weight soon after the first hour following birth. Undertake an initial examination to detect any major physical abnormality and to identify any problems that require referral. Ensure that any examination or treatment of the baby is undertaken with the consent of the parents and either in their presence or, if this is not possible, with their knowledge. ## Neonatal resuscitation In the first minutes after birth, evaluate the condition of the baby – specifically respiration, heart rate and tone – in order to determine whether resuscitation is needed according to nationally accredited guidelines on neonatal resuscitation. All relevant healthcare professionals caring for women during birth should attend annually a course in neonatal resuscitation that is consistent with nationally accredited guidelines on neonatal resuscitation. In all birth settings: bear in mind that it will be necessary to call for help if the baby needs resuscitation, and plan accordingly ensure that there are facilities for resuscitation, and for transferring the baby to another location if necessary develop emergency referral pathways for both the woman and the baby, and implement these if necessary. If a newborn baby needs basic resuscitation, start with air. Minimise separation of the baby and mother, taking into account the clinical circumstances. Throughout an emergency situation in which the baby needs resuscitation, allocate a member of the healthcare team to talk with, and offer support to, the woman and any birth companion(s). ## Care of babies in the presence of meconium In the presence of any degree of meconium: do not suction the baby's upper airways (nasopharynx and oropharynx) before birth of the shoulders and trunk do not suction the baby's upper airways (nasopharynx and oropharynx) if the baby has normal respiration, heart rate and tone do not intubate if the baby has normal respiration, heart rate and tone. If there has been significant meconium (see recommendation 1.5.2 in the section on presence of meconium) and the baby does not have normal respiration, heart rate and tone, follow nationally accredited guidelines on neonatal resuscitation, including early laryngoscopy and suction under direct vision. If there has been significant meconium and the baby is healthy, closely observe the baby within a unit with immediate access to a neonatologist. Perform these observations at 1 and 2 hours of age and then 2‑hourly until 12 hours of age. If there has been non‑significant meconium, observe the baby at 1 and 2 hours of age in all birth settings. If any of the following are observed after any degree of meconium, ask a neonatologist to assess the baby (transfer both the woman and baby if they are at home or in a freestanding midwifery unit, following the general principles for transfer of care): respiratory rate above 60 per minute the presence of grunting heart rate below 100 or above 160 beats/minute capillary refill time above 3 seconds body temperature of 38°C or above, or 37.5°C on 2 occasions 30 minutes apart -xygen saturation below 95% (measuring oxygen saturation is optional after non‑significant meconium) presence of central cyanosis, confirmed by pulse oximetry if available. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes. Explain the findings to the woman, and inform her about what to look out for and who to talk to if she has any concerns. ## Babies born to women with prelabour rupture of the membranes at term Closely observe any baby born to a woman with prelabour rupture of the membranes (more than 24 hours before the onset of established labour) at term for the first 12 hours of life (at 1 hour, 2 hours, 6 hours and 12 hours) in all settings. Include assessment of: temperature heart rate respiratory rate presence of respiratory grunting significant subcostal recession presence of nasal flare presence of central cyanosis, confirmed by pulse oximetry if available skin perfusion assessed by capillary refill floppiness, general wellbeing and feeding.If any of these are observed, ask a neonatologist to assess the baby (transfer both the woman and baby if they are at home or in a freestanding midwifery unit, following the general principles for transfer of care). Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes. If there are no signs of infection in the woman, do not give antibiotics to either the woman or the baby, even if the membranes have been ruptured for over 24 hours. If there is evidence of infection in the woman, prescribe a full course of broad‑spectrum intravenous antibiotics. Advise women with prelabour rupture of the membranes to inform their healthcare professionals immediately of any concerns they have about their baby's wellbeing in the first 5 days after birth, particularly in the first 12 hours when the risk of infection is greatest. Do not perform blood, cerebrospinal fluid and/or surface culture tests in an asymptomatic baby. Refer a baby with any symptom of possible sepsis, or born to a woman who has evidence of chorioamnionitis, to a neonatal care specialist immediately. # Care of the woman after birth ## Initial assessment Carry out the following observations of the woman after birth: Record her temperature, pulse and blood pressure. Transfer the woman (with her baby) to obstetric‑led care if any of the relevant indications listed in the recommendation on ongoing assessment are met. Uterine contraction and lochia. Examine the placenta and membranes: assess their condition, structure, cord vessels and completeness. Transfer the woman (with her baby) to obstetric‑led care if the placenta is incomplete. Early assessment of the woman's emotional and psychological condition in response to labour and birth. Successful voiding of the bladder. Assess whether to transfer the woman (with her baby) to obstetric‑led care after 6 hours if her bladder is palpable and she is unable to pass urine.If transferring the woman to obstetric‑led care, follow the general principles for transfer of care. ## Perineal care Define perineal or genital trauma caused by either tearing or episiotomy as follows: first degree – injury to skin only second degree – injury to the perineal muscles but not the anal sphincter third degree – injury to the perineum involving the anal sphincter complex: a – less than 50% of external anal sphincter thickness torn b – more than 50% of external anal sphincter thickness torn c – internal anal sphincter torn. fourth degree – injury to the perineum involving the anal sphincter complex (external and internal anal sphincter) and anal epithelium. Before assessing for genital trauma: explain to the woman what is planned and why -ffer inhalational analgesia ensure good lighting position the woman so that she is comfortable and so that the genital structures can be seen clearly. Perform the initial examination gently and with sensitivity. It may be done in the immediate period after birth. If genital trauma is identified after birth, offer further systematic assessment, including a rectal examination. Include the following in a systematic assessment of genital trauma: further explanation of what is planned and why confirmation by the woman that tested effective local or regional analgesia is in place visual assessment of the extent of perineal trauma to include the structures involved, the apex of the injury and assessment of bleeding a rectal examination to assess whether there has been any damage to the external or internal anal sphincter if there is any suspicion that the perineal muscles are damaged. Ensure that the timing of this systematic assessment does not interfere with mother–baby bonding unless the woman has bleeding that requires urgent attention. Assist the woman to adopt a position that allows adequate visual assessment of the degree of trauma and for repair. Only maintain this position for as long as necessary for systematic assessment and repair. If it is not possible to adequately assess the trauma, transfer the woman (with her baby) to obstetric‑led care, following the general principles for transfer of care. Seek advice from a more experienced midwife or obstetrician if there is uncertainty about the nature or extent of the trauma. Transfer the woman (with her baby) to obstetric‑led care (following the general principles for transfer of care) if the repair needs further surgical or anaesthetic expertise. Document the systematic assessment and its results fully, possibly pictorially. All relevant healthcare professionals should attend training in perineal/genital assessment and repair, and ensure that they maintain these skills. Undertake repair of the perineum as soon as possible to minimise the risk of infection and blood loss. When carrying out perineal repair: ensure that tested effective analgesia is in place, using infiltration with up to 20 ml of 1% lidocaine or equivalent top up the epidural or insert a spinal anaesthetic if necessary. If the woman reports inadequate pain relief at any point, address this immediately. Advise the woman that in the case of first‑degree trauma, the wound should be sutured in order to improve healing, unless the skin edges are well opposed. Advise the woman that in the case of second‑degree trauma, the muscle should be sutured in order to improve healing. If the skin is opposed after suturing of the muscle in second‑degree trauma, there is no need to suture it. If the skin does require suturing, use a continuous subcuticular technique. Undertake perineal repair using a continuous non‑locked suturing technique for the vaginal wall and muscle layer. Use an absorbable synthetic suture material to suture the perineum. Offer rectal non‑steroidal anti‑inflammatory drugs routinely after perineal repair of first‑ and second‑degree trauma provided these drugs are not contraindicated. Observe the following basic principles when performing perineal repairs: Repair perineal trauma using aseptic techniques. Check equipment and count swabs and needles before and after the procedure. Good lighting is essential to see and identify the structures involved. Ensure that difficult trauma is repaired by an experienced practitioner in theatre under regional or general anaesthesia. Insert an indwelling catheter for 24 hours to prevent urinary retention. Ensure that good anatomical alignment of the wound is achieved and that consideration is given to the cosmetic results. Carry out rectal examination after completing the repair to ensure that suture material has not been accidentally inserted through the rectal mucosa. After completion of the repair, document an accurate detailed account covering the extent of the trauma, the method of repair and the materials used. Give the woman information about the extent of the trauma, pain relief, diet, hygiene and the importance of pelvic‑floor exercises (see the NICE guideline on pelvic floor dysfunction). # Putting this guideline into practice NICE has produced tools and resources to help you put this guideline into practice. Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities. Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils. Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once). Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations. Here are some pointers to help organisations put NICE guidelines into practice: . Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away. . Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally. . Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision. . Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation. . Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases. . For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals. . Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support. . Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners. NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information. Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context Giving birth is a life‑changing event. The care that a woman receives during labour has the potential to affect her – both physically and emotionally, in the short and longer term – and the health of her baby. Good communication, support and compassion from staff, and having her wishes respected, can help her feel in control of what is happening and contribute to making birth a positive experience for the woman and her birth companion(s). This guideline covers the care of healthy women who go into labour at term (37+0 to 41+6 weeks). About 700,000 women give birth in England and Wales each year, of whom about 40% are having their first baby. Most of these women are healthy and have a straightforward pregnancy. Almost 90% of women will give birth to a single baby after 37 weeks of pregnancy, with the baby presenting head first. About two‑thirds of women go into labour spontaneously. Therefore, most women giving birth in England and Wales are covered by this guideline. Since the original guideline was published in 2007, the number of women giving birth in England and Wales each year has risen, the rate of intervention (instrumental births and caesarean section) has increased slightly, and there has been some reconfiguration of services. The decision to update the guideline in 2014 was made based on developments in the NHS and new evidence becoming available that could affect the recommendations from 2007. It is important that the woman is given information and advice about all available settings when she is deciding where to have her baby, so that she is able to make a fully informed decision. This includes information about outcomes for the different settings. It is also vital to recognise when transfer of care from midwifery‑led care to obstetric‑led care is indicated because of increased risk to the woman and/or her baby resulting from complications that have developed during labour. Uncertainty and inconsistency of care has been identified in a number of areas, such as choosing place of birth, care during the latent first stage of labour, fetal assessment and monitoring during labour (particularly cardiotocography compared with intermittent auscultation) and management of the third stage of labour. These and other related topics are addressed in the guideline. The guideline is intended to cover the care of healthy women with uncomplicated pregnancies entering labour at low risk of developing intrapartum complications. In addition, recommendations are included that address the care of women who start labour as 'low risk' but who go on to develop complications. These include the care of women with prelabour rupture of membranes at term, care of the woman and baby when meconium is present, indications for continuous cardiotocography, interpretation of cardiotocograph traces, and management of retained placenta and postpartum haemorrhage. Aspects of intrapartum care for women at risk of developing intrapartum complications are covered by a range of NICE guidelines on specific conditions and a further guideline is planned on the intrapartum care of women at high risk of complications during pregnancy and the intrapartum period.# Recommendations for research The guideline committee has made the following recommendations for research. # Models of midwifery-led care In December 2021, we stood down this recommendation for research as continuity of care in maternity services is now a national policy in the UK following on from the National Maternity Review on Better Births and the subsequent Maternity Transformation Programme. # Effect of information giving on place of birth How does the provision of accurate, evidence‑based information affect women's decision‑making processes and choice of place of birth? ## Why this is important A report by Coxon et al. (2013) identifies in detail why women make choices about where to give birth and how these choices can be influenced. Influences may include written and verbal information (both online and from midwives and doctors), previous experience, and word‑of‑mouth advice from friends and family. The Birthplace study concluded that giving birth outside an obstetric unit is the optimal choice for low‑risk women. This finding should be used to restructure the way in which information is provided, so that it is presented in a more accurate, less risk‑based way in order to support women's choices. This change should be evaluated in a quantitative observational study and/or qualitative study that records any changes in women's choice‑making about place of birth. Outcomes include understanding why and how women make choices about where to give birth and how this can influence the provision of appropriate and accessible information, a measure of informed decision‑making, and fearfulness and absence of fearfulness when choosing place of birth. # Long‑term consequences of planning birth in different settings What are the long‑term consequences for women and babies of planning birth in different settings? ## Why this is important The long‑term consequences of birth experiences and birth outcomes are poorly understood, particularly in relation to place of birth. A large population‑based observational study would compare women's experiences and outcomes in different birth settings (with subgroup analysis by mode of birth) in relation to the wellbeing of the women and their children over different periods of time (for example, 2, 5, 10, 15, 20 and 30 years). A secondary analysis could compare different providers where birth philosophies are different. Outcomes would be compared by accessing medical records and through qualitative interviews. Primary outcomes are long‑term physical morbidity, pain after birth, readmission to hospital, infection, psychological morbidity (for example, postnatal depression, bonding, relationship breakdown with partner, fear of giving birth in future) and breastfeeding rates. Secondary outcomes are impact on attachment between mother and child, obesity in children, autoimmune disease, chronic illness, educational achievement and family functioning. # Education about the latent first stage of labour Does enhanced education specifically about the latent first stage of labour increase the number of nulliparous women who wait until they are in established labour before attending the obstetric or midwifery unit (or calling the midwife to a home birth), compared with women who do not receive this education? ## Why this is important Studies show that antenatal education about labour and birth in general makes a difference to some birth outcomes, but there is limited evidence focusing on education about the latent first stage of labour specifically. The aim of this study (randomised controlled trial or prospective observational study) would be to compare 2 groups of women experiencing their first labour and birth: a group who receive an education session in late pregnancy covering what to expect in the latent first stage of labour and how to recognise the onset of established labour, and a group who have not received this focused education. Primary outcomes would be mode of birth, satisfaction with the birth experience and the woman's physical and emotional wellbeing after birth. Secondary outcomes would be use of pharmacological pain relief, use of oxytocin to augment labour, and time from first contact in confirmed established labour to birth. # Postpartum haemorrhage What is the most effective treatment for primary postpartum haemorrhage? ## Why this is important There is uncertainty about the most effective drug treatments and dosage regimes, and about which other treatments should be used, for women who develop a postpartum haemorrhage. The most effective sequencing of interventions is also uncertain. The psychological impact of postpartum haemorrhage for women can be significant, and identifying the approach that minimises this impact is important. Randomised controlled trials comparing different dosage regimes for oxytocin and misoprostol, as well as comparisons with ergometrine and carboprost, are needed. Trials of mechanical measures such as intrauterine balloons or interventional radiology as early second‑line treatment (rather than an alternative drug treatment) are also needed. Alternatively, a trial comparing the effectiveness of a complex intervention (for example, an educational component, sequence of interventions, immediate feedback and quality improvements) compared with standard care could be undertaken. Important outcomes include blood and blood product transfusion, need for further intervention, need for hysterectomy and psychological outcomes for the woman.# Appendix A: Adverse outcomes Adverse outcome: in order to be able to count enough adverse events to be able to say that the results recorded are not just a result of chance, the Birthplace UK (2011) study used a composite definition of 'adverse outcome'. The definition includes the following outcomes: stillbirth during labour, death of the baby in the first week after birth, neonatal encephalopathy (disordered brain function caused by oxygen deprivation before or during birth), meconium aspiration syndrome, and physical birth injuries (brachial plexus injury and bone fractures). The term 'serious medical problems' has been used to describe this composite outcome in the guideline recommendations. Outcome Actual number of babies affected out of (63,955 to 64,535*; number per 1,000) Percentage of all adverse outcomes measured Stillbirth after start of care in labour -ut of 64,535 (0.22 per 1,000) Death of the baby in the first week after birth -ut of 64,292 (0.28 per 1,000) Neonatal encephalopathy (disordered brain function caused by oxygen deprivation before or during birth) (clinical diagnosis) -ut of 63,955 (1.6 per 1,000) Meconium aspiration syndrome (the baby breathes meconium into their lungs) -ut of 63,955 (1.3 per 1,000) Brachial plexus injury -ut of 63,955 (0.38 per 1,000) Bone fractures -ut of 63,955 (0.17 per 1,000) Total (of all outcomes included in the 'adverse outcome' composite measure) -ut of 63,955 to 64,535) (approximately 4 per 1,000) Note: Each of the categories above are mutually exclusive and outcomes listed higher in the table take precedence over outcomes listed lower down. For example, if a baby with neonatal encephalopathy died within 7 days the outcome is classified as an early neonatal death. - Denominator varies because of missing values. Does not equal 100% because of rounding.

Cospas-Sarsat Cospas-Sarsat is an international satellite-based search and rescue (SAR) distress alert detection and information distribution system, established by Canada, France, the United States, and the former Soviet Union in 1979. The system consists of both a ground segment and a space segment: - Distress radiobeacons - SAR signal processors aboard satellites - Satellite downlink receiving and signal processing stations called LUTs (Local User Terminalss) - Mission Control Centres that distribute distress alert data generated by the LUTs - Rescue Coordination Centres that coordinate SAR response to a distress situation The space segment of the Cospas-Sarsat system currently consists of SAR processors aboard 4 geosynchronous satellites called GEOSARs and 5 low-earth polar orbit satellites called LEOSARs. # Background Information Cospas-Sarsat began tracking the two original types of distress radiobeacons in 1982. Specifically, these were: - EPIRBs (Emergency Position-Indicating Radio Beacons), which signal maritime distress; and - ELTs (Emergency Locator Transmitters), which signal aircraft distress More recently, a new type of distress radiobeacon became available (in 2003 in the USA) : - PLBs (Personal Locator Beacons), are for personal use and are intended to indicate a person in distress who is away from normal emergency services (i.e. 9-1-1) The four founding countries led development of the 406 MHz marine EPIRB for detection by the system. The EPIRB was seen as a key advancement in SAR technology in the perilous maritime environment. The aviation community had already been using the 121.5 MHz frequency for distress, so ELTs for general aviation were created using 121.5 MHz, a frequency listened to by the airlines. Military beacons using the 243.0 MHz frequency could also be detected by the system. The design of distress radiobeacons as a whole has evolved significantly since 1982; the newest 406 MHz beacons incorporate GPS receivers; such beacons transmit highly accurate positions of distress almost instantly to SAR agencies via the GEOSAR satellites. The advent of such beacons has created the current motto of SAR agencies --- "Taking the 'Search' out of Search and Rescue." (See MEOSAR below.) COSPAS is an acronym for the Russian words "Cosmicheskaya Sistyema Poiska Avariynich Sudov", which translates to "Space System for the Search of Vessels in Distress". SARSAT is an acronym for Search And Rescue Satellite-Aided Tracking. Cospas-Sarsat is an element of the Global Maritime Distress Safety System (GMDSS). Automatic-activating EPIRBs are now required on International Convention for the Safety of Life at Sea (SOLAS) ships, commercial fishing vessels, and all passenger ships, are designed to transmit to a Rescue Coordination Centre a vessel identification and an accurate location of the vessel from anywhere in the world. # Phase-Out of 121.5 & 243.0 MHz Distress Radiobeacons Starting on 1 February 2009, the Cospas-Sarsat System will cease processing signals from the deprecated 121.5 MHz and 243 MHz beacons; from then on only signals from 406 MHz beacons will be processed. The switch to 406 MHz is expected to result in a substantial reduction in wasted use of SAR resources on false alerts while simultaneously increasing the responsiveness of the system for real distress cases. # System Composition The ground segment of the system consists of: - Distress radiobeacons - Satellite downlink receiving and signal processing stations called LUTs (Local User Terminalss) - Mission Control Centres that distribute distress alert data generated by the LUTs - Rescue Coordination Centres that coordinate SAR response to a distress situation The space segment of the system consists of: - SAR signal processors aboard satellites ## Space Segment (SAR Processors - SARP) The Cospas-Sarsat system space segment consists of SAR signal processors (SARP) aboard: - 4 geosynchronous satellites called GEOSARs, and - 5 low-earth polar orbit satellites LEOSARs. A SARP is basically a box stuck on the side of a satellite. In this way, SARP are considered a secondary payload onboard satellites with more lucrative core purposes. See the Technical Information below for lists of SARP and their associated satellites. ## Ground Segment The satellites are monitored by receiving stations equipped with satellite-tracking satellite dishes called LUTs (Local User Terminals). Each nation's LUTs are monitored by an MCC (Mission Control Centre), a data distribution clearinghouse that distributes alert information to the various Rescue Coordination Centres (RCCs). # Technical Information ## Doppler Processing The Cospas-Sarsat system was made possible by the advent of Doppler processing. LUTs detecting non-geostationary satellites profit from the apparent Doppler frequency shift heard by LEOSAR and MEOSAR satellites as they pass over a beacon transmitting at a fixed frequency. The apparent frequency shift allows processing to triangulate the position of the distress radiobeacon. See Doppler Processing article at Cospas-Sarsat and Wiki on Doppler radar. ## LEOSAR LEOSAR predates the GEOSAR system, and it complements it. LEOSAR satellites are monitored by 44 LEOLUTs (Low Earth Orbit Local User Terminals). The complementary LEOSAR satellites provide periodic coverage of the entire earth with an emphasis on polar regions. The LEOSAR satellites operate in a store-and-forward mode for 406 MHz signals --- they store distress signals and forward them to the next LEOLUT ground station they overfly. The 4-satellite polar-orbit constellation LEOSAR system provides frequent coverage of the poles with approximately 100 minute orbits. Up until mid-2007, two of the LEOSAR satellites were Cospas satellites provided by the former Soviet Union and operated by the Russian Federation. However, they were recently taken offline, and now, only the American SARSAT satellites are in service. COSPAS satellites characteristically orbit at 1000 km altitude. The five operational LEOSAR satellites are the Sarsat satellites provided by the United States NOAA. These orbit at an altitude of 850 km. They are: - Sarsat-7 SARP aboard NOAA-15 - Sarsat-8 SARP aboard NOAA-16 - Sarsat-9 SARP aboard NOAA-17 - Sarsat-10 SARP aboard NOAA-18 - Sarsat-11 SARP aboard METOP-A ## GEOSAR The GEOSAR satellites are monitored by 16 GEOLUTs (Geostationary Earth Orbit Local User Terminals.) The GEOSAR satellites provide continuous coverage of the entire earth below 70 degrees latitude with a view toward the equatorial sky. Some locations have poor radio reception toward the GEOSAR satellites and polar regions are not well covered. SARP are installed on the following geostationary satellites: - The GOES geostationary satellites GOES-East at 75° W and GOES-West at 135° W - The INSAT-3A geostationary satellite at 93.5° E - The Meteosat Second Generation (MSG) geostationary satellite MSG-2 fixed over the Prime Meridian ## Beacon Technical Information Main Article: Distress radiobeacons Typical rescue beacon radios transmit a 5 watt signal for 0.5 seconds once every 50 seconds. Most of these terminals sold since 1997 include a GPS receiver so they can report precise GPS lat-lon location. Aircraft distress radiobeacons (ELTs) are automatically activated by acceleration switches after a crash, while maritime radiobeacons (EPIRBs) are normally activated by contact with sea water. The "406 MHz" channel is 170 kHz wide and centered at 406.05 MHz. The message is either a 112-bit "short" message or a 144-bit "long" message both including 49 bits of identification plus position information. # MEOSAR Supporters of the Cospas-Sarsat system are working to add a new capability called MEOSAR (Medium Earth Orbit Search and Rescue satellites.) In its current (project) form, it is being called the Distress Alerting Satellite System (DASS) by NASA. This system will put SAR processors aboard the GPS satellite constellation the Galileo positioning system constellation. MEOSAR satellites will be able to provide near-instantaneous detection, identification, receipt of encoded position, and determination of Doppler triangulated position of 406 MHz beacons (exclusively.) MEOSAR assets will report signals from Cospas-Sarsat search and rescue beacons in the 406.0–406.1 MHz band. There is also the possibility that the system will be able to download information back to the distress radiobeacon via the GPS downlink. # Rescue Statistics In 2004, the Cospas-Sarsat system provided assistance in rescuing 1,748 people in 466 SAR events.

This work is licensed under a Creative Commons Attribution 4.0 International License.- It can take at least 7-14 days, and sometimes longer, after symptom onset for antibodies to develop, therefore the use of serology POC tests in the early phase of infection can result in a false negative COVID-19 diagnosis at a time when patients are most infectious (i.e. a negative result does not rule out infection). - False negative interpretations may occur in elderly and immunocompromised patients, who are unable to mount an adequate antibody response. - Since serology POC tests do not detect virus, a positive or negative result does not determine whether a person is infectious. - Positive results may be due to past or recent infection with SARS-CoV-2 or from COVID-19 vaccination. - Most POC serology tests are unable to differentiate antibodies developed from previous infection from those generated in response to COVID-19 vaccination. Given the rapid expansion of COVID-19 vaccination, this further limits the use of serology POC tests. - As with other COVID-19 serological platforms, false positive results may occur if these kits cross-react with antibodies from recent or past exposure to other coronaviruses, including human coronaviruses. - Other infections, as well as non-infectious conditions (e.g. rheumatoid factor-positive diseases), may also cause false positive results. - False positive results are more likely in areas of low prevalence and low vaccine uptake. The local epidemiology and pretest probability of the individual (i.e. clinical and epidemiological risk factors) need to be taken into consideration when interpreting POC serology results.# Introduction Point-of-care (POC) serology tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), detect the human antibody response to infection or vaccination and not the virus itself. Most are qualitative immunochromatographic (lateral-flow)-based assays that detect IgG+/-IgM from a finger prick blood sample and can provide results in less than 30 minutes. While there is widespread interest in adopting POC serology tests for COVID-19, there are currently significant limitations to this testing modality, including the incomplete understanding of the immunological response in COVID-19, suboptimal clinical validation data, uncertain correlation (or lack thereof) with clinical laboratorybased serology tests and wide variability in performance among different POC tests. Many of the key points outlined below also apply to laboratory-based COVID-19 serology testing. # Current position for acute diagnostics Serology POC tests for COVID-19 are not recommended for use as a diagnostic tool for acute infection and only three products are approved by Health Canada to date. In general, these tests are not able to detect antibodies until at least a week or more after symptoms have started, and therefore are not suitable for diagnosis of acute SARS-CoV-2 infection at this time. We recommend that nucleic acid detection (e.g. real-time polymerase chain reaction) remain the first line test for the diagnosis of acute SARS-CoV-2 infection, as advised by the World Health Organization (1). # ADVISORY COMMITTEE STATEMENT - Due to the visual interpretations of most POC serology tests, false positive and negative results may arise from incorrect or subjective reading. - As per recommendations from the National Advisory Committee on Immunization, there is no indication for serology prior to or after COVID-19 vaccination. - Any kits used need to be thoroughly evaluated for performance characteristics (sensitivity, specificity) before being used clinically, including in-field use conditions. An evolving and exceptional use for POC serology testing may be considered when laboratory-based serology testing is not available or is unable to meet the necessary rapid turnaround times to help identify COVID-19 patients most likely to benefit from anti-SARS-CoV-2 monoclonal antibody therapy. Serology testing currently has limited clinical utility; however, some jurisdictions have recommended its use to help inform treatment decisions for COVID-19 patients, as early clinical trial data showed that some monoclonal antibody therapies (e.g. casirivimab + imdevimab) were most effective in seronegative patients. Even in this context, we recommend that serology POC tests be performed in a laboratory setting to help mitigate some of the risks outlined above and validated before use as described below. When possible, laboratory-based SARS-CoV-2 serology testing is preferred. # Current position for use as "immunity certificates or passports" There has been ongoing discussion around the use of antibody testing as evidence of immunity to facilitate individual movement in public areas and to permit international travel. The knowledge around immunity to SARS-CoV-2 is rapidly evolving; however, at this time, the correlates of protection and duration of immunity are not well understood. As such, we do not recommend using serology, including POC tests, for determining individual immunity or for establishing exemptions from public health measures. # Key points - Since there is currently no correlate of protection, it is unknown if the levels of antibodies detected by serology POC tests are sufficient for protection. - Since POC tests do not provide a quantitative result, their utility may be limited even once a correlate of protection is established. - COVID-19 antibodies may persist for at least six months; however, the rate at which antibodies decline over time varies by age, immune status of the individual and severity of disease. - Binding antibodies detected by serology POC tests may not correlate with neutralizing (i.e. protective) antibodies. - Since it takes at least 7-14 days (longer in some individuals) to mount an antibody response, a negative result does not exclude an active infection or rule out infectiousness; therefore, it does not confirm that an individual cannot transmit SARS-CoV-2. Serology tests should not replace molecular (or antigen) testing for travel or other screening purposes. - Although reinfection or infection after vaccination is relatively rare, a positive serology result does not guarantee protection from infection, especially with intense exposures and the emergence of SARS-CoV-2 variants that have immune escape potential. - Since serology POC tests do not detect T-cell mediated immunity to SARS-CoV-2, which is also important for long-term protection, a negative result is not proof that an individual is not immune. - Modelling has shown that public health measures, such as masking and physical distancing, will be required to control the spread of SARS-CoV-2 until the time that population vaccine coverage and adequate population immunity are achieved. Thus, a positive serology result, including from POC testing, may provide a false sense of protection from SARS-CoV-2 infection at the individual level. # Important considerations is implementing point-of-care testing The role of serology in the diagnosis of SARS-CoV-2 infection, patient management and immunity testing is of limited utility. Once the dynamics of the serological response in COVID-19 are better understood and a correlate of protection is identified, serology may play an important role in the population-based public health response. If serology POC testing is implemented for a specific purpose (e.g. testing for monoclonal antibody treatment), the following should be considered: - Extensive validation of the test(s) against a gold standard (viral neutralization assays or another laboratory-based serological assay). Performance characteristics (sensitivity, specificity, positive and negative predictive values, crossreaction to other coronaviruses) should be established using sera from patients infected with SARS-CoV-2 (ancestral and variants), other respiratory viruses, including seasonal coronaviruses, and healthy controls. - Provide adequate training to healthcare/laboratory workers to perform the test and interpret the result. - Performing a risk assessment for infection with SARS-CoV-2 and bloodborne infections for the operator. We recommend that universal protective measures to prevent bloodborne pathogen transmission (at a minimum, gloves and gowns) be used when running POC assays until the risk to the operator can be formally assessed. - Establishing an ongoing quality control/quality assurance program prior to implementation. - Establishing provisions to ensure the capture of testing data for individual patient records and surveillance purposes and the requirement for participation in external quality assessment to maintain high-quality testing. Based on currently available information, the Canadian Public Health Laboratory Network recommends that COVID-19 POC serological assays not be used for routine clinical or immunity testing at this time. In line with recommendations by the National Advisory Committee on Immunization (2), serology testing should not be used to document vaccination status or to assess response to COVID-19 vaccination. As more information becomes available on immunological correlates of protection, duration of immunity, test performance and assays are validated against gold standard serological methods, clinical application of POC assays will be re-evaluated. Molecular testing, such as real-time polymerase chain reaction, remains the primary test method for laboratory confirmation of acute SARS-CoV-2 infection and diagnosis of COVID-19.

TobraDex Synonyms / Brand Names: # Dosing and Administration One or two drops instilled into the conjunctival sac(s) every four to six hours. During the initial 24 to 48 hours, the dosage may be increased to one or two drops every two (2) hours. Frequency should be decreased gradually as warranted by improvement in clinical signs. Care should be taken not to discontinue therapy prematurely. Not more than 20 mL should be prescribed initially and the prescription should not be refilled without further evaluation. FDA Package Insert Resources Indications, Contraindications, Side Effects, Drug Interactions, etc. Calculate Creatine Clearance On line calculator of your patients Cr Cl by a variety of formulas. Convert pounds to Kilograms On line calculator of your patients weight in pounds to Kg for dosing estimates. Publication Resources Recent articles, WikiDoc State of the Art Review, Textbook Information Trial Resources Ongoing Trials, Trial Results Guidelines & Evidence Based Medicine Resources US National Guidelines, Cochrane Collaboration, etc. Media Resources Slides, Video, Images, MP3, Podcasts, etc. Patient Resources Discussion Groups, Handouts, Blogs, News, etc. International Resources en Español # FDA Package Insert Resources Indications Contraindications Side Effects Precautions Overdose Instructions for Administration How Supplied Pharmacokinetics and Molecular Data FDA label FDA on TobraDex Return to top # Publication Resources Most Recent Articles on TobraDex Review Articles on TobraDex Articles on TobraDex in N Eng J Med, Lancet, BMJ WikiDoc State of the Art Review Textbook Information on TobraDex Return to top # Trial Resources Ongoing Trials with TobraDex at Clinical Trials.gov Trial Results with TobraDex Return to top # Guidelines & Evidence Based Medicine Resources US National Guidelines Clearinghouse on TobraDex Cochrane Collaboration on TobraDex Cost Effectiveness of TobraDex Return to top # Media Resources Powerpoint Slides on TobraDex Images of TobraDex Podcasts & MP3s on TobraDex Videos on TobraDex Return to top # Patient Resources Patient Information from National Library of Medicine Patient Resources on TobraDex Discussion Groups on TobraDex Patient Handouts on TobraDex Blogs on TobraDex TobraDex in the News TobraDex in the Marketplace Return to top # International Resources TobraDex en Español Return to top Adapted from the FDA Package Insert.

3-Methylcrotonyl-CoA carboxylase deficiency 3-Methylcrotonyl-CoA carboxylase deficiency (3MCC deficiency), also known as 3-Methylcrotonylglycinuria type 1 or BMCC deficiency is an inherited disorder in which the body is unable to process certain proteins properly. People with this disorder have inadequate levels of an enzyme that helps break down proteins containing the amino acid leucine. This condition affects an estimated 1 in 50,000 individuals worldwide. # Presentation Infants with this disorder appear normal at birth but usually develop signs and symptoms during the first year of life or in early childhood. The characteristic features of this condition, which can range from mild to life-threatening, include feeding difficulties, recurrent episodes of vomiting and diarrhea, excessive tiredness (lethargy), and weak muscle tone (hypotonia). If untreated, this disorder can lead to delayed development, seizures, and coma. Early detection and lifelong management (following a low-protein diet and using appropriate supplements) may prevent many of these complications. In some cases, people with gene mutations that cause 3-methylcrotonyl-CoA carboxylase deficiency never experience any signs or symptoms of the disorder. The characteristic features of this condition are similar to those of Reye syndrome, a severe disorder that develops in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections. # Genetics The MCCC1 and MCCC2 genes make protein subunits that come together to form an enzyme called 3-methylcrotonyl-CoA carboxylase. This enzyme plays an essential role in breaking down proteins from the diet. Specifically, the enzyme is responsible for the fourth step in processing leucine. If a mutation in the MCCC1 or MCCC2 gene reduces or eliminates the activity of 3-methylcrotonyl-CoA carboxylase, the body is unable to process leucine properly. As a result, toxic byproducts of leucine processing build up to harmful levels, damaging the brain and nervous system. This condition is inherited in an autosomal recessive pattern. # Screening It is one of the 29 conditions currently recommended for newborn screening by the American College of Medical Genetics.

Test # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Test is {{{aOrAn}}} {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of {{{indication}}}. Common adverse reactions include {{{adverseReactions}}}. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) There is limited information regarding Test FDA-Labeled Indications and Dosage (Adult) in the drug label. ## Off-Label Use and Dosage (Adult) # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Test FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) # Contraindications There is limited information regarding Test Contraindications in the drug label. # Warnings There is limited information regarding Test Warnings' in the drug label. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Test Clinical Trials Experience in the drug label. ## Postmarketing Experience There is limited information regarding Test Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Test Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Test in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Test in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Test during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Test in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Test in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Test in geriatric settings. ### Gender There is no FDA guidance on the use of Test with respect to specific gender populations. ### Race There is no FDA guidance on the use of Test with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Test in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Test in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Test in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Test in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Test Administration in the drug label. ### Monitoring There is limited information regarding Test Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Test and IV administrations. # Overdosage There is limited information regarding Test overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action ## Structure ## Pharmacodynamics ## Pharmacokinetics ## Nonclinical Toxicology # Clinical Studies # How Supplied ## Storage # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol Alcohol-Test interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names # Look-Alike Drug Names There is limited information regarding Test Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price

TADA2L Transcriptional adapter 2-alpha is a protein that in humans is encoded by the TADA2A gene. # Function Many DNA-binding transcriptional activator proteins enhance the initiation rate of RNA polymerase II-mediated gene transcription by interacting functionally with the general transcription machinery bound at the basal promoter. Adaptor proteins are usually required for this activation, possibly to acetylate and destabilize nucleosomes, thereby relieving chromatin constraints at the promoter. The protein encoded by this gene is a transcriptional activator adaptor and has been found to be part of the PCAF histone acetylase complex. Two transcript variants encoding different isoforms have been identified for this gene. # Interactions TADA2L has been shown to interact with GCN5L2, TADA3L and Myc.

Particle physics Particle physics is a branch of physics that studies the elementary constituents of matter and radiation, and the interactions between them. It is also called high energy physics, because many elementary particles do not occur under normal circumstances in nature, but can be created and detected during energetic collisions of other particles, as is done in particle accelerators. Research in this area has produced a long list of particles. # Subatomic Particles Modern particle physics research is focused on subatomic particles, which have less structure than atoms. These include atomic constituents such as electrons, protons, and neutrons (protons and neutrons are actually composite particles, made up of quarks), particles produced by radiative and scattering processes, such as photons, neutrinos, and muons, as well as a wide range of exotic particles. Strictly speaking, the term particle is a misnomer because the dynamics of particle physics are governed by quantum mechanics. As such, they exhibit wave-particle duality, displaying particle-like behavior under certain experimental conditions and wave-like behavior in others (more technically they are described by state vectors in a Hilbert space; see quantum field theory). Following the convention of particle physicists, "elementary particles" refer to objects such as electrons and photons, with the understanding that these "particles" display wave-like properties as well. All the particles and their interactions observed to date can almost be described entirely by a quantum field theory called the Standard Model. The Standard Model has 40 species of elementary particles (24 fermions, 12 vector bosons, and 4 scalar bosons), which can combine to form composite particles, accounting for the hundreds of other species of particles discovered since the 1960s. The Standard Model has been found to agree with almost all the experimental tests conducted to date. However, most particle physicists believe that it is an incomplete description of nature, and that a more fundamental theory awaits discovery. In recent years, measurements of neutrino mass have provided the first experimental deviations from the Standard Model. Particle physics has had a large impact on the philosophy of science. Some particle physicists adhere to reductionism, a point of view that has been criticized and defended by philosophers and scientists. Part of the debate is described below. # History The idea that all matter is composed of elementary particles dates to at least the 6th century BC. The philosophical doctrine of atomism was studied by ancient INDIAN philosophers such as maharshi Kanad. In the 19th century John Dalton, through his work on stoichiometry, concluded that each element of nature was composed of a single, unique type of particle. Dalton and his contemporaries believed these were the fundamental particles of nature and thus named them atoms, after the Greek word atomos, meaning "indivisible". However, near the end of the century, physicists discovered that atoms were not, in fact, the fundamental particles of nature, but conglomerates of even smaller particles. The early 20th century explorations of nuclear physics and quantum physics culminated in proofs of nuclear fission in 1939 by Lise Meitner (based on experiments by Otto Hahn), and nuclear fusion by Hans Bethe in the same year. These discoveries gave rise to an active industry of generating one atom from another, even rendering possible (although not profitable) the transmutation of lead into gold. They also led to the development of nuclear weapons. Throughout the 1950s and 1960s, a bewildering variety of particles were found in scattering experiments. This was referred to as the "particle zoo". This term was deprecated after the formulation of the Standard Model during the 1970s in which the large number of particles was explained as combinations of a (relatively) small number of fundamental particles. # The Standard Model The current state of the classification of elementary particles is the Standard Model. It describes the strong, weak, and electromagnetic fundamental forces, using mediating gauge bosons. The species of gauge bosons are the gluons, ] and Z bosons, and the photons. The model also contains 24 fundamental particles, which are the constituents of matter. Finally, it predicts the existence of a type of boson known as the Higgs boson, which has yet to be discovered. # Experiment In particle physics, the major international laboratories are: - Brookhaven National Laboratory, located on Long Island, USA. Its main facility is the Relativistic Heavy Ion Collider which collides heavy ions such as gold ions and polarized protons. It is the world's first heavy ion collider, and the world's only polarized proton collider. - Budker Institute of Nuclear Physics (Novosibirsk, Russia)] - CERN, located on the French-Swiss border near Geneva. Its main project is now LHC, or the Large Hadron Collider, which is currently under construction. The LHC will be in operation in 2008 and will be the world's most energetic collider upon completion. Earlier facilities include LEP, the Large Electron Positron collider, which was stopped in 2001 and which is now dismantled to give way for LHC; and SPS, or the Super Proton Synchrotron. - DESY, located in Hamburg, Germany. Its main facility is HERA, which collides electrons or positrons and protons. - Fermilab, located near Chicago, USA. Its main facility is the Tevatron, which collides protons and antiprotons and is presently the highest energy particle collider in the world. - KEK The High Energy Accelerator Research Organization of Japan located in Tsukuba, Japan. It is the home of a number of interesting experiments such as K2K, a neutrino oscillation experiment and Belle, an experiment measuring the CP-symmetry violation in the B-meson. - SLAC, located near Palo Alto, USA. Its main facility is PEP-II, which collides electrons and positrons. Many other particle accelerators exist. The techniques required to do modern experimental particle physics are quite varied and complex, constituting a subspecialty nearly completely distinct from the theoretical side of the field. See Category:Experimental particle physics for a partial list of the ideas required for such experiments. # Theory Theoretical particle physics attempts to develop the models, theoretical framework, and mathematical tools to understand current experiments and make predictions for future experiments. See also theoretical physics. There are several major efforts in theoretical particle physics today and each includes a range of different activities. The efforts in each area are interrelated. There are five most important states in particle theory: one of the major activities in theoretical particle physics is the attempt to better understand the standard model and its tests. By extracting the parameters of the standard model from experiments with less uncertainty, this work probes the limits of the standard model and therefore expands our understanding of nature. These efforts are made challenging by the difficult nature of calculating many quantities in quantum chromodynamics. Some theorists making these efforts refer to themselves as phenomenologists and may use the tools of quantum field theory and effective field theory. Others make use of lattice field theory and call themselves lattice theorists. Another major effort is in model building where model builders develop ideas for what physics may lie beyond the standard model (at higher energies or smaller distances). This work is often motivated by the hierarchy problem and is constrained by existing experimental data. It may involve work on supersymmetry, alternatives to the Higgs mechanism, extra spatial dimensions (such as the Randall-Sundrum models), Preon theory, combinations of these, or other ideas. A third major effort in theoretical particle physics is string theory. String theorists attempt to construct a unified description of quantum mechanics and general relativity by building a theory based on small strings, and branes rather than particles. If the theory is successful, it may be considered a "Theory of Everything". There are also other areas of work in theoretical particle physics ranging from particle cosmology to loop quantum gravity. This division of efforts in particle physics is reflected in the names of categories on the preprint archive : hep-th (theory), hep-ph (phenomenology), hep-ex (experiments), hep-lat (lattice gauge theory). # Public Policy Experimental results in particle physics are often obtained using enormous particle accelerators which are very expensive and require large amounts of government funding. Because of this, particle physics research involves issues of public policy. # The Future Particle physicists internationally agree on the most important goals of particle physics research in the near and intermediate future. The overarching goal, which is pursued in several distinct ways, is to find and understand what physics may lie beyond the standard model. There are several powerful experimental reasons to expect new physics, including dark matter and neutrino mass. There are also theoretical hints that this new physics should be found at accessible energy scales. Most importantly, though, there may be unexpected and unpredicted surprises which will give us the most opportunity to learn about nature. Much of the efforts to find this new physics are focused on new collider experiments. A (relatively) near term goal is the completion of the Large Hadron Collider (LHC) in 2008 which will continue the search for the Higgs boson, supersymmetric particles, and other new physics. An intermediate goal is the construction of the International Linear Collider (ILC) which will complement the LHC by allowing more precise measurements of the properties of newly found particles. A decision for the technology of the ILC has been taken in August 2004, but the site has still to be agreed upon. Additionally, there are important non-collider experiments which also attempt to find and understand physics beyond the standard model. One important non-collider effort is the determination of the neutrino masses since these masses may arise from neutrinos mixing with very heavy particles. In addition, cosmological observations provide many useful constraints on the dark matter, although it may be impossible to determine the exact nature of the dark matter without the colliders. Finally, lower bounds on the very long lifetime of the proton put constraints on Grand Unification Theories at energy scales much higher than collider experiments will be able to probe any time soon.

Ganirelix # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Ganirelix is a Endocrine-Metabolic Agent that is FDA approved for the treatment of inhibition of premature LH surges in women undergoing controlled ovarian hyperstimulation. Common adverse reactions include Abdominal Pain (gynecological), Headache, Ovarian Hyperstimulation Syndrome, Vaginal Bleeding. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Ganirelix Acetate Injection is indicated for the inhibition of premature LH surges in women undergoing controlled ovarian hyperstimulation. ### Dosage - After initiating FSH therapy on Day 2 or 3 of the cycle, Ganirelix Acetate Injection 250 mcg may be administered subcutaneously once daily during the mid to late portion of the follicular phase. By taking advantage of endogenous pituitary FSH secretion, the requirement for exogenously administered FSH may be reduced. Treatment with Ganirelix Acetate should be continued daily until the day of hCG administration. When a sufficient number of follicles of adequate size are present, as assessed by ultrasound, final maturation of follicles is induced by administering hCG. The administration of hCG should be withheld in cases where the ovaries are abnormally enlarged on the last day of FSH therapy to reduce the chance of developing OHSS (Ovarian Hyperstimulation Syndrome). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ganirelix in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ganirelix in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Ganirelix in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ganirelix in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ganirelix in pediatric patients. # Contraindications - Ganirelix Acetate Injection is contraindicated under the following conditions: - Known hypersensitivity to Ganirelix Acetate or to any of its components. - Known hypersensitivity to GnRH or any other GnRH analog. - Known or suspected pregnancy # Warnings - Ganirelix Acetate Injection should be prescribed by physicians who are experienced in infertility treatment. Before starting treatment with Ganirelix Acetate, pregnancy must be excluded. Safe use of Ganirelix Acetate during pregnancy has not been established ### Precautions - Special care should be taken in women with signs and symptoms of active allergic conditions. Cases of hypersensitivity reactions, including anaphylactoid reactions, have been reported, as early as with the first dose, during post-marketing surveillance . In the absence of clinical experience, Ganirelix Acetate treatment is not advised in women with severe allergic conditions. - The packaging of this product contains natural rubber latex which may cause allergic reactions. - Prior to therapy with Ganirelix Acetate Injection, patients should be informed of the duration of treatment and monitoring procedures that will be required. The risk of possible adverse reactions should be discussed. - Ganirelix Acetate should not be prescribed if the patient is pregnant. - A neutrophil count ≥ 8.3 ( x 109/L) was noted in 11.9% (up to 16.8 x 109/L) of all subjects treated within the adequate and well-controlled clinical trials. In addition, downward shifts within the Ganirelix Acetate Injection group were observed for hematocrit and total bilirubin. The clinical significance of these findings was not determined. # Adverse Reactions ## Clinical Trials Experience - The safety of Ganirelix Acetate Injection was evaluated in two randomized, parallel-group, multicenter controlled clinical studies. Treatment duration for Ganirelix Acetate ranged from 1 to 14 days. Table IV represents adverse events (AEs) from first day of Ganirelix Acetate administration until confirmation of pregnancy by ultrasound at an incidence of ≥ 1% in Ganirelix Acetate-treated subjects without regard to causality. - Ongoing clinical follow-up studies of 283 newborns of women administered Ganirelix Acetate Injection were reviewed. There were three neonates with major congenital anomalies and 18 neonates with minor congenital anomalies. The major congenital anomalies were: hydrocephalus/meningocele, omphalocele, and Beckwith-Wiedemann Syndrome. The minor congenital anomalies were: nevus, skin tags, sacral sinus, hemangioma, torticollis/asymmetric skull, talipes, supernumerary digit finger, hip subluxation, torticollis/high palate, occiput/abnormal hand crease, hernia umbilicalis, hernia inguinalis, hydrocele, undescended testis, and hydronephrosis. The causal relationship between these congenital anomalies and Ganirelix Acetate is unknown. Multiple factors, genetic and others (including, but not limited to ICSI, IVF, gonadotropins, progesterone) may confound ART (Assisted Reproductive Technology) procedures. ## Postmarketing Experience - During post-marketing surveillance, rare cases of hypersensitivity reactions, including anaphylactoid reactions, have been reported, as early as with the first dose # Drug Interactions - No formal drug-drug interaction studies have been performed. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X - Ganirelix Acetate Injection is contraindicated in pregnant women. When administered from Day 7 to near term to pregnant rats and rabbits at doses up to 10 and 30 mcg/day (approximately 0.4 to 3.2 times the human dose based on body surface area), Ganirelix Acetate increased the incidence of litter resorption. There was no increase in fetal abnormalities. No treatment-related changes in fertility, physical, or behavioral characteristics were observed in the offspring of female rats treated with Ganirelix Acetate during pregnancy and lactation. - The effects on fetal resorption are logical consequences of the alteration in hormonal levels brought about by the antigonadotropic properties of this drug and could result in fetal loss in humans. Therefore, this drug should not be used in pregnant women Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ganirelix in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Ganirelix during labor and delivery. ### Nursing Mothers - Ganirelix Acetate Injection should not be used by lactating women. It is not known whether this drug is excreted in human milk. ### Pediatric Use There is no FDA guidance on the use of Ganirelix with respect to pediatric patients. ### Geriatic Use - Clinical studies with Ganirelix Acetate Injection did not include a sufficient number of subjects aged 65 and over. ### Gender There is no FDA guidance on the use of Ganirelix with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ganirelix with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Ganirelix in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Ganirelix in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Ganirelix in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Ganirelix in patients who are immunocompromised. # Administration and Monitoring ### Administration - Ganirelix Acetate Injection is supplied in a sterile, prefilled syringe and is intended for SUBCUTANEOUS administration only. - Wash hands thoroughly with soap and water. - The most convenient sites for SUBCUTANEOUS injection are in the abdomen around the navel or upper thigh. - The injection site should be swabbed with a disinfectant to remove any surface bacteria. Clean about two inches around the point where the needle will be inserted and let the disinfectant dry for at least one minute before proceeding. - With syringe held upward, remove needle cover. - Pinch up a large area of skin between the finger and thumb. Vary the injection site a little with each injection. - The needle should be inserted at the base of the pinched-up skin at an angle of 45–90° to the skin surface. - When the needle is correctly positioned, it will be difficult to draw back on the plunger. If any blood is drawn into the syringe, the needle tip has penetrated a vein or artery. If this happens, withdraw the needle slightly and reposition the needle without removing it from the skin. Alternatively, remove the needle and use a new, sterile, prefilled syringe. Cover the injection site with a swab containing disinfectant and apply pressure; the site should stop bleeding within one or two minutes. - Once the needle is correctly placed, depress the plunger slowly and steadily, so the solution is correctly injected and the skin is not damaged. - Pull the syringe out quickly and apply pressure to the site with a swab containing disinfectant. - Use the sterile, prefilled syringe only once and dispose of it properly. ### Monitoring There is limited information regarding Monitoring of Ganirelix in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Ganirelix in the drug label. # Overdosage - There have been no reports of overdosage with Ganirelix Acetate Injection in humans. # Pharmacology ## Mechanism of Action - The pulsatile release of GnRH stimulates the synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The frequency of LH pulses in the mid and late follicular phase is approximately 1 pulse per hour. These pulses can be detected as transient rises in serum LH. At midcycle, a large increase in GnRH release results in an LH surge. The midcycle LH surge initiates several physiologic actions including: ovulation, resumption of meiosis in the oocyte, and luteinization. Luteinization results in a rise in serum progesterone with an accompanying decrease in estradiol levels. - Ganirelix Acetate acts by competitively blocking the GnRH receptors on the pituitary gonadotroph and subsequent transduction pathway. It induces a rapid, reversible suppression of gonadotropin secretion. The suppression of pituitary LH secretion by Ganirelix Acetate is more pronounced than that of FSH. An initial release of endogenous gonadotropins has not been detected with Ganirelix Acetate, which is consistent with an antagonist effect. Upon discontinuation of Ganirelix Acetate, pituitary LH and FSH levels are fully recovered within 48 hours. ## Structure - Ganirelix Acetate Injection is a synthetic decapeptide with high antagonistic activity against naturally occurring gonadotropin-releasing hormone (GnRH). Ganirelix Acetate is derived from native GnRH with substitutions of amino acids at positions 1, 2, 3, 6, 8, and 10 to form the following molecular formula of the peptide: N-acetyl-3-(2-naphthyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridyl)-D-alanyl-L-seryl-L-tyrosyl-N9,N10-diethyl-D-homoarginyl-L-leucyl-N9,N10-diethyl-L-homoarginyl-L-prolyl-D-alanylamide acetate. The molecular weight for Ganirelix Acetate is 1570.4 as an anhydrous free base. The structural formula is as follows: Ganirelix Acetate - Ganirelix Acetate Injection is supplied as a colorless, sterile, ready-to-use, aqueous solution intended for SUBCUTANEOUS administration only. Each sterile, prefilled syringe contains 250 mcg/0.5 mL of Ganirelix Acetate, 0.1 mg glacial acetic acid, 23.5 mg mannitol, and water for injection adjusted to pH 5.0 with acetic acid, NF and/or sodium hydroxide, NF. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Ganirelix in the drug label. ## Pharmacokinetics - The pharmacokinetic parameters of single and multiple injections of Ganirelix Acetate Injection in healthy adult females are summarized in Table I. Steady-state serum concentrations are reached after 3 days of treatment. The pharmacokinetics of Ganirelix Acetate are dose-proportional in the dose range of 125 to 500 mcg. - Ganirelix Acetate is rapidly absorbed following subcutaneous injection with maximum serum concentrations reached approximately one hour after dosing. The mean absolute bioavailability of Ganirelix Acetate following a single 250 mcg subcutaneous injection to healthy female volunteers is 91.1%. - The mean (SD) volume of distribution of Ganirelix Acetate in healthy females following intravenous administration of a single 250-mcg dose is 43.7 (11.4) liters (L). In vitro protein binding to human plasma is 81.9%. - Following single-dose intravenous administration of radiolabeled Ganirelix Acetate to healthy female volunteers, Ganirelix Acetate is the major compound present in the plasma (50–70% of total radioactivity in the plasma) up to 4 hours and urine (17.1–18.4% of administered dose) up to 24 hours. Ganirelix Acetate is not found in the feces. The 1–4 peptide and 1–6 peptide of Ganirelix Acetate are the primary metabolites observed in the feces. - On average, 97.2% of the total radiolabeled Ganirelix Acetate dose is recovered in the feces and urine (75.1% and 22.1%, respectively) over 288 h following intravenous single dose administration of 1 mg -Ganirelix Acetate. Urinary excretion is virtually complete in 24 h, whereas fecal excretion starts to plateau 192 h after dosing. - The pharmacokinetics of Ganirelix Acetate Injection have not been determined in special populations such as geriatric, pediatric, renally impaired and hepatically impaired patients. - Formal in vivo or in vitro drug-drug interaction studies have not been conducted (see PRECAUTIONS). Since Ganirelix Acetate can suppress the secretion of pituitary gonadotropins, dose adjustments of exogenous gonadotropins may be necessary when used during controlled ovarian hyperstimulation (COH). ## Nonclinical Toxicology - Long-term toxicity studies in animals have not been performed with Ganirelix Acetate Injection to evaluate the carcinogenic potential of the drug. Ganirelix Acetate did not induce a mutagenic response in the Ames test (S. typhimurium and E. coli) or produce chromosomal aberrations in in vitro assay using Chinese Hamster Ovary cells. # Clinical Studies - The efficacy of Ganirelix Acetate Injection was established in two adequate and well-controlled clinical studies which included women with normal endocrine and pelvic ultrasound parameters. The studies intended to exclude subjects with polycystic ovary syndrome (PCOS) and subjects with low or no ovarian reserve. One cycle of study medication was administered to each randomized subject. For both studies, the administration of exogenous recombinant FSH 150 IU daily was initiated on the morning of Day 2 or 3 of a natural menstrual cycle. Ganirelix Acetate Injection was administered on the morning of Day 7 or 8 (Day 6 of recombinant FSH administration). The dose of recombinant FSH administered was adjusted according to individual responses starting on the day of initiation of Ganirelix Acetate. Both recombinant FSH and Ganirelix Acetate were continued daily until at least three follicles were 17 mm or greater in diameter at which time hCG was administered. Following hCG administration, Ganirelix Acetate and recombinant FSH administration were discontinued. Oocyte retrieval, followed by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), was subsequently performed. - In a multicenter, double-blind, randomized, dose-finding study, the safety and efficacy of Ganirelix Acetate Injection were evaluated for the prevention of LH surges in women undergoing COH with recombinant FSH. Ganirelix Acetate Injection doses ranging from 62.5 mcg to 2000 mcg and recombinant FSH were administered to 332 patients undergoing COH for IVF (see TABLE II). Median serum LH on the day of hCG administration decreased with increasing doses of Ganirelix Acetate. Median serum E2 (17β-estradiol) on the day of hCG administration was 1475, 1110, and 1160 pg/mL for the 62.5-, 125-, and 250-mcg doses, respectively. Lower peak serum E2 levels of 823, 703, and 441 pg/mL were seen at higher doses of Ganirelix Acetate 500, 1000, and 2000 mcg, respectively. The highest pregnancy and implantation rates were achieved with the 250-mcg dose of Ganirelix Acetate Injection as summarized in Table II. - Transient LH rises alone were not deleterious to achieving pregnancy with Ganirelix Acetate at doses of 125 mcg (3/6 subjects) and 250 mcg (1/1 subjects). In addition, none of the subjects with LH rises ≥ 10 mIU/mL had premature luteinization indicated by a serum progesterone above 2 ng/mL. - A multicenter, open-label, randomized study was conducted to assess the efficacy and safety of Ganirelix Acetate Injection in women undergoing COH. Follicular phase treatment with Ganirelix Acetate 250 mcg was studied using a luteal phase GnRH agonist as a reference treatment. A total of 463 subjects were treated with Ganirelix Acetate by subcutaneous injection once daily starting on Day 6 of recombinant FSH treatment. Recombinant FSH was maintained at 150 IU for the first 5 days of ovarian stimulation and was then adjusted by the investigator on the sixth day of gonadotropin use according to individual responses. The results for the Ganirelix Acetate arm are summarized in Table III. - The mean number of days of Ganirelix Acetate treatment was 5.4 (2–14). - The midcycle LH surge initiates several physiologic actions including: ovulation, resumption of meiosis in the oocyte, and luteinization. In 463 subjects administered Ganirelix Acetate Injection 250 mcg, a premature LH surge prior to hCG administration, (LH rise ≥ 10 mIU/mL with a significant rise in serum progesterone > 2 ng/mL, or a significant decline in serum estradiol) occurred in less than 1% of subjects. # How Supplied - Ganirelix Acetate Injection is supplied in: - Disposable, sterile, ready for use, prefilled 1 mL glass syringes containing 250 mcg/0.5 mL aqueous solution of Ganirelix Acetate closed with a rubber piston that does not contain latex. Each Ganirelix Acetate sterile, prefilled syringe is affixed with a 27 gauge × ½-inch needle closed by a needle shield of natural rubber latex and is blister-packed. ## Storage - Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) . Protect from light. # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL - 250 MCG/0.5 ML PREFILLED SYRINGE CARTON NDC 0052-0301-51 250 mcg Sterile Prefilled Syringe 27 gauge by 1/2" needle Ganirelix Acetate Injection 250 mcg/0.5 mL For Subcutaneous Use Rx only ### Ingredients and Appearance # Patient Counseling Information - Prior to therapy with Ganirelix Acetate Injection, patients should be informed of the duration of treatment and monitoring procedures that will be required. The risk of possible adverse reactions should be discussed (see ADVERSE REACTIONS). - Ganirelix Acetate should not be prescribed if the patient is pregnant. # Precautions with Alcohol - Alcohol-Ganirelix interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Antagon® # Look-Alike Drug Names There is limited information regarding Ganirelix Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price

IKBKAP IKBKAP (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein) is a human gene encoding the IKAP protein, which is ubiquitously expressed at varying levels in all tissue types, including brain cells. The IKAP protein is thought to participate as a sub-unit in the assembly of a six-protein putative human holo-Elongator complex, which allows for transcriptional elongation by RNA polymerase II. Further evidence has implicated the IKAP protein as being critical in neuronal development, and directs that decreased expression of IKAP in certain cell types is the molecular basis for the severe, neurodevelopmental disorder familial dysautonomy. Other pathways that have been connected to IKAP protein function in a variety of organisms include tRNA modification, cell motility, and cytosolic stress signalling. Homologs of the IKBKAP gene have been identified in multiple other Eukaryotic model organisms. Notable homologs include Elp1 in yeast, Ikbkap in mice, and D-elp1 in fruit flies. The fruit fly homolog (D-elp1) has RNA-dependent RNA polymerase activity and is involved in RNA interference. The IKBKAP gene is located on the long (q) arm of chromosome 9 at position 31, from base pair 108,709,355 to base pair 108,775,950. # Function and mechanism Originally, it was proposed that the IKBKAP gene in humans was encoding a scaffolding protein (IKAP) for the IκB enzyme kinase (IKK) complex, which is involved in pro-inflammatory cytokine signal transduction in the NF-κB signalling pathway. However, this was subsequently disproven when researchers applied a gel filtration method and could not identify IKK complexes contained in fractions with IKAP, thus dissociating IKAP from having a role in the NF-κB signalling pathway. Later, it was discovered that IKAP functions as a cytoplasmic scaffold protein in the mammalian JNK-signalling pathway which is activated in response to stress stimuli. In an in vivo experiment, researchers showed direct interaction between IKAP and JNK induced by the application of stressors such as ultraviolet light and TNF-α (a pro-inflammatory cytokine). IKAP is now also widely acknowledged to have a role in transcriptional elongation in humans. The RNA polymerase II holoenzyme constitutes partly of a multi-subunit histone acetyltransferase element known as the RNA polymerase II elongator complex, of which IKAP is one subunit. The association of the elongator complex with RNA polymerase II holoenzyme is necessary for subsequent binding to nascent pre-mRNA of certain target genes, and thus their successful transcription. Specifically, within the cell, the depletion of functional elongater complexes due to low IKAP expression has been found to have a profound effect on transcription of genes involved in cell migration. In yeast, experimental data shows the elongator complex functioning in a variety of processes — from exocytosis to tRNA modification. This finding demonstrates that the function of the elongator complex is not conserved among species. # Related conditions ## Familial Dysautonomia Familial dysautonomia (also known as “Riley-Day syndrome”) is a complex congenital neurodevelopmental disease, characterized by unusually low numbers of neurons in the sensory and autonomic nervous systems. The resulting symptoms of patients include gastrointestinal dysfunction, scoliosis, and pain insensitivity. This disease is especially prevalent in the Ashkenazi Jewish population, where 1/3600 live births present familial dysautonomia. By 2001, the genetic cause of familial dysautonomia was localized to a dysfunctional region spanning 177kb on chromosome 9q31. With the use of blood samples from diagnosed patients, the implicated region was successfully sequenced. The IKBKAP gene, one of the five genes identified in that region, was found to have a single-base mutation in over 99.5% of cases of familial dysautonomia seen. The single-base mutation, overwhelmingly noted as a transition from cytosine to thymine, is present in the 5’ splice donor site of intron 20 in the IKBKAP pre-mRNA. This prevents recruitment of splicing machinery, and thus exon 19 is spliced directly to exon 21 in the final mRNA product – exon 20 is removed from the pre-mRNA with the introns. The unintentional removal of an exon from the final mRNA product is termed exon skipping. Therefore, there is a decreased level of functional IKAP protein expression within affected tissue. However, this disorder is tissue-specific. Lymphoblasts, even with the mutation present, may continue to express some functional IKAP protein. In contrast, brain tissue with the single-base mutation in the IKBKAP gene predominantly express a resulting truncated, mutant IKAP protein which is nonfunctional. The exact mechanism for how the familial dysautonomia phenotype is induced due to reduced IKAP expression is unclear; still, as a protein involved in transcriptional regulation, there have been a variety of proposed mechanisms. One such theory suggests that critical genes in the development of wild-type sensory and autonomic neurons are improperly transcribed. An extension of this research suggests that genes involved in cell migration are impaired in the nervous system, creating a foundation for this disorder. In a small number of reported familial dysautonomia cases, researchers have identified other mutations that cause a change in amino acids (the building blocks of proteins). In these cases, arginine is replaced by proline at position 696 in the IKAP protein's chain of amino acids (also written as Arg696Pro), or proline is replaced by leucine at position 914 (also written as Pro914Leu). Together, these mutations cause the resulting IKAP protein to malfunction. As an autosomal recessive disorder, two mutated alleles of the IKBKAP gene are required for the disorder to manifest. However, despite the predominance of the same single-base mutation being the reputed cause of familial dysautonomia, the severity of the affected phenotype varies within and between families. Kinetin (6-furfurylaminopurine) has been found to have the capacity to repair the splicing defect and increase wild-type IKBKAP mRNA expression in vivo. Further research is still required to assess the fitness of kinetin as a possible future oral treatment. # Model organisms Model organisms have been used in the study of IKBKAP gene function. ## Mouse A conditional knockout mouse line, called Ikbkaptm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out and two phenotypes were reported. No homozygous mutant embryos were identified during gestation, and in a separate study, none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no significant abnormalities were observed in these animals. ## Saccharomyces cerevisiae The homologous protein for IKAP in yeast is Elp1, with 29% identity and 46% similarity detected between the proteins. The yeast Elp1 protein is a subunit of a three-protein RNA polymerase II-associated elongator complex. ## Drosophila melanogaster The IKBKAP gene homolog in fruit flies is the CG10535 gene, encoding the D-elp1 protein — the largest of three subunits making the RNA polymerase II core elongator complex. This subunit was found to have RNA-dependent RNA polymerase activity, through which it could synthesize double-stranded RNA from single-stranded RNA templates. This activity was observed in a D-elp1 protein-dependent step converting transposon RNA into double-stranded RNA for processing by Dcr-2 (a Drosophila dicer), involved in further RNA degradation and silencing.

Keratitis # Overview Keratitis is a condition in which the eye's cornea is inflamed. Superficial keratitis involves the superficial layers of the cornea. After healing, this form of keratitis does not generally leave a scar. Deep keratitis involves the deeper layers of the cornea, leaving a scar upon healing that impairs vision if on or near the visual axis. Keratitis has multiple causes, one of which is an infection of a present or previous herpes simplex virus secondary to an upper respiratory infection, involving cold sores. Symptoms of keratitis include red eyes, sensitivity to light, and uncomfortable eyes. In the later stages of more severe cases, there can be strong pain, loss of vision, blurry vision, and pus. Microbial keratitis should be managed as bacterial keratitis until proven otherwise. Steroids are indicated in the management of keratitis to reduce inflammation that may damage the eye. # Classification Superficial keratitis involves the superficial layers of the cornea. After healing, this form of keratitis does not generally leave a scar. Deep keratitis involves deeper layers of the cornea, leaving a scar upon healing that impairs vision if on or near the visual axis. # Pathophysiology Keratitis has multiple causes, one of which is an infection of a present or previous herpes simplex virus secondary to an upper respiratory infection, involving cold sores. ## Pathogens - Amoebic keratitis. Amoebic infection of the cornea is the most serious corneal infection, usually affecting soft contact lens wearers. It is usually caused by Acanthamoeba. On May 25, 2007, the CDC issued a health advisory due to increased risk of Acanthamoeba keratitis (AK)infection associated with use of Advanced Medical Optics (AMO) Complete Moisture Plus Multi-Purpose eye solution. See CDC Advisory - Bacterial keratitis. Bacterial infection of the cornea can follow from an injury or from wearing contact lenses. The bacteriums usually involved are Staphylococcus aureus and for contact lens wearers Pseudomonas aeruginosa. - Fungal keratitis (cf. Fusarium, causing recent incidences of keratitis through the possible vector of Bausch & Lomb ReNu with MoistureLoc contact lens solution) - Viral keratitis - Herpes simplex keratitis. Viral infection of the cornea is often caused by the herpes simplex virus which frequently leaves what is called a 'dendritic ulcer'. - Herpes zoster keratitis ## Other - Exposure keratitis - Photokeratitis - keratitis due to intense ultraviolet radiation exposure (e.g. snow blindness or welder's arc eye.) - Ulcerative keratitis - Contact lens acute red eye (CLARE) - a non-ulcerative sterile keratitis associated with colonization of Gram-negative bacteria on contact lenses - Severe allergic response may lead to corneal inflammation and ulceration (i.e. vernal keratoconjunctivitis). - Drug Induced - Afatinib, Cyclopentolate, Diclofenac (ophthalmic), Doxorubicin Hydrochloride, Emedastine Difumarate, Moxifloxacin ophthalmic, Naphazoline , Nitisinone, Panitumumab, Pramipexole # Causes ## Life Threatening Causes Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. - Small pox ## Common Causes - Adenovirus - Contact lens - Herpes simplex virus - Injury ## Causes by Organ System ## Causes in Alphabetical Order - Acanthamoeba - Aciclovir - Adenovirus - Afatinib - Amaurosis fugax - Arc eye - Aspergillus fumigatus - Atopic dermatitis - Bacillus cereus - Balamuthia mandrillaris - Behcet disease - Betaxolol (ophthalmic) - Bimatoprost - Brimonidine (ophthalmic) - Bromfenac - Brucellosis - Candida - Canine herpesvirus - Cogan syndrome - Confocal laser scanning microscopy - Congenital syphilis - Conjunctivitis - Connexin - Contact lens - Contact lens acute red eye - Contaminated water - Corneal dystrophy - Corneal transplantation - Corneal ulcer - Corynebacterium diphtheriae - Crab louse - Cyclopentolate - Dendritic ulcer - Diclofenac (ophthalmic) - Dorzolamide - Doxorubicin hydrochloride - Dry eyes - Ectrodactyly-ectodermal dysplasia-cleft syndrome - Ectropion - Emedastine difumarate - Enterobacteria - Enterovirus - Epidermolysis bullosa - Epinastine - Erythema elevatum diutinum - Erythema multiforme - Exophthalmos - Facial nerve paralysis - Facioscapulohumeral muscular dystrophy - Feline viral rhinotracheitis - Fungal keratitis - Fusarium - Graves' disease - Graves ophthalmopathy - Haemophilus influenzae - Henoch-Schönlein purpura - Herpes simplex keratitis - Herpes simplex virus infection - Herpes zoster - Herpesviridae - Herpetic keratitis - Hydroxypropyl cellulose - Ichthyosis - Immune reconstitution inflammatory syndrome - Incontinentia pigmenti - Injury - Jellyfish stings - Keratitis-ichthyosis-deafness syndrome - Keratoconjunctivitis - Keratoconjunctivitis sicca - KID syndrome - Lagophthalmos - LASIK - Latanoprost - Late congenital syphilitic oculopathy - Lepromatous leprosy - Listeria - Lyme disease - Mansonella ozzardi - Measles - Microsporidiosis - Moraxella - Moxifloxacin ophthalmic - Mycobacterium - Mycobacterium boenickei - Mycobacterium brisbanense - Mycobacterium houstonense - Mycobacterium neworleansense - Naegleria infection - Naphazoline - Natamycin - Neisseria gonorrhea - Nepafenac - Nitisinone - Nocardiosis - Non-steroidal anti-inflammatory drug (topical) - Ocular rosacea - Oculotect - Oculovestibuloauditory syndrome - Olopatadine - Onchocerciasis - Orthokeratology - Orthopoxvirus - Panitumumab - Pannus - Parechovirus - Phlyctenular keratoconjunctivitis - Phosgene oxime - Photokeratitis - Phycomycosis - Pityriasis rubra pilaris - Plesiomonas shigelloides - Pramipexole - Pseudomonas aeruginosa - Psittacosis - Radial keratotomy - Reactive arthritis - Reiter's syndrome - Relapsing polychondritis - ReNu - Rheumatoid arthritis - Rheumatoid vasculitis - Ribonucleotide reductase - Scedosporium apiospermum - Scleritis - Scopolamine - Serratia marcescens - Shigella - Sicca syndrome - Sjögren's syndrome - Smallpox - Snow blindness - Staphylococcus aureus - Staphylococcus epidermidis - Stevens-Johnson syndrome - Streptococcus pneumoniae - Superior limbic keratoconjunctivitis - Syphilis - Systemic lupus erythematosus - Thygeson's superficial punctate keratopathy - Topical anesthetic - Toxic epidermal necrolysis - Trachoma - Travoprost - Trifluridine - Type II tyrosinemia - Ultraviolet radiation - Unoprostone - Vaccinia - Varicella-zoster virus - Vasculitis - Vernal keratoconjunctivitis - Vidarabine - Vitamin A deficiency - Xeroderma pigmentosum # Symptoms The symptoms are often very similar to those of conjunctivitis, an inflammation of the conjunctiva, and photophobia. The eye turns very red and there may be sensitivity to light, and the eye may feel uncomfortable. In the later stages of more severe cases, there can be strong pain, loss of vision/blurriness, and pus may form. # Diagnosis Effective diagnosis is important in detecting this condition and subsequent treatment as keratitis is sometimes mistaken for an allergic conjunctivitis. # Treatment - Treatment depends on the cause of the keratitis. - Microbial keratitis should be managed as bacterial keratitis until proven otherwise. - Steroids are indicated in the management of keratitis to reduce inflammation that may damage the eye. ## Antimicrobial regimens ### Bacterial Keratitis - 1. Causative pathogens - Pseudomonas aeruginosa - Staphylococcus epidermidis - Staphylococcus aureus - Streptococcus pneumoniae - Serratia spp. - Hemophilus spp. - Moraxella spp. - Neisseria gonorrhea - Corynebacterium diphtheriae - Listeria spp. - Shigella spp. - Nocardia spp. - Mycobacterium spp. - 2. Empiric antimicrobial therapy - Preferred regimen (1): Ciprofloxacin 0.3% ophthalmic ointment q15min for 6 hours then q30min for the remainder of day 1 then q1h on day 2, then q4h on days 3-14 - Preferred regimen (2): Ofloxacin 0.3% ophthalmic ointment q2h for 2-3 weeks - Preferred regimen (3): Levofloxacin 1.5% ophthalmic ointment q2h for 2-3 weeks - Preferred regimen (4): Moxifloxacin 0.5% q1h on day 1 then q2h on day 2 then q4h on days 3-14 - Preferred regimen (5): Gatifloxacin 0.3% q1h on day 1 then q2h on day 2 then q4h on days 3-14 - Preferred regimen (6): Cefazolin 5% q30min to q1h on day 1 then q2h on day 2 then q4h on days 3-14 AND Tobramycin 5% ophthalmic ointment q1h on day 1 then q2h on day 2 then q4h on days 3-14 OR Gentamicin 1.5% ophthalmic ointment q30min to q1h on day 1 then q1h on day 2 then q4h on days 3-14) - Alternative regimen (1), unresponsive keratitis: Vancomycin 5% q30 min on day 1 then q2h on day 2 then q4h on days 3-14 AND Amikacin 5% q1h on day 1 then q2h on day 2 then q4h on days 3-14 - Alternative regimen (2): Erythromycin 0.5% ophthalmic ointment qhs for 1 week AND (Amikacin 5% AND/OR Vancomycin 5% q30 min on day 1 then q2h on day 2 then q4h on days 3-14) - Note (1) : Subconjunctival antibiotics may be helpful where there is imminent scleral spread or perforation or in cases where adherence to the treatment regimen is questionable. - Note (2) : Systemic therapy is necessary for suspected gonococcal infection. - 3. Pathogen-directed antimicrobial therapy - 3.1 Non-streptococcal gram-positive bacteria - Preferred regimen (1): Moxifloxacin 0.5% q1h on day 1 then q2h on day 2 then q4h on days 3-14 - Preferred regimen (2): Gatifloxacin 0.3% q1h on day 1 then q2h on day 2 then q4h on days 3-14 - Preferred regimen (3): Ciprofloxacin 0.3% ophthalmic ointment q15min for 6 hours then q30min for the remainder of day 1 then q1h on day 2, then q4h on days 3-14 - Preferred regimen (4): Ofloxacin 0.3% ophthalmic ointment q2h for 2-3 weeks - Preferred regimen (5): Levofloxacin 1.5% ophthalmic ointment q2h for 2-3 weeks - Preferred regimen (6): Cefazolin 5% q30min to q1h on day 1 then q1h on day 2 then q4h on days 3-14 AND Tobramycin 5% ophthalmic ointment q1h on day 1 then q2h on day 2 then q4h on days 3-14 - 3.2 Streptococcus pneumoniae - Preferred regimen (1): Moxifloxacin 0.5% q1h on day 1 then q2h on day 2 then q4h on days 3-14 - Preferred regimen (2): Gatifloxacin 0.3% q1h on day 1 then q2h on day 2 then q4h on days 3-14 - Preferred regimen (3): Ciprofloxacin 0.3% ophthalmic ointment q15min for 6 hours then q30min for the remainder of day 1 then q1h on day 2, then q4h on days 3-14 - Preferred regimen (4): Ofloxacin 0.3% ophthalmic ointment q2h for 2-3 weeks - Preferred regimen (5): Levofloxacin 1.5% ophthalmic ointment q2h for 2-3 weeks - Preferred regimen (6): Cefazolin 5% q30min to q1h on day 1 then q1h on day 2 then q4h on days 3-14 AND Tobramycin 5% ophthalmic ointment q1h on day 1 then q2h on day 2 then q4h on days 3-14 - Alternative regimen (unresponsive keratitis): Vancomycin 5% q30 min on day 1 then q2h on day 2 then q4h on days 3-14 AND Amikacin 5% q1h on day 1 then q2h on day 2 then q4h on days 3-14 - 3.3 Nocardia spp. - Preferred regimen (1): Vancomycin 5% q30 min on day 1 then q2h on day 2 then q4h on days 3-14 AND Amikacin 5% q1h on day 1 then q2h on day 2 then q4h on days 3-14 - Preferred regimen (2): Erythromycin 0.5% ophthalmic ointment qhs for 1 week AND (Amikacin 5% AND/OR Vancomycin 5% q30 min on day 1 then q2h on day 2 then q4h on days 3-14) - 3.4 Gram-negative bacteria - Preferred regimen (1): Moxifloxacin 0.5% q1h on day 1 then q2h on day 2 then q4h on days 3-14 - Preferred regimen (2): Gatifloxacin 0.3% q1h on day 1 then q2h on day 2 then q4h on days 3-14 - Preferred regimen (3): Ciprofloxacin 0.3% ophthalmic ointment q15min for 6 hours then q30min for the remainder of day 1 then q1h on day 2, then q4h on days 3-14 - Preferred regimen (4): Ofloxacin 0.3% ophthalmic ointment q2h for 2-3 weeks - Preferred regimen (5): Levofloxacin 1.5% ophthalmic ointment q2h for 2-3 weeks - Preferred regimen (6): Cefazolin 5% q30min to q1h on day 1 then q1h on day 2 then q4h on days 3-14 AND Tobramycin 5% ophthalmic ointment q1h on day 1 then q2h on day 2 then q4h on days 3-14 - 3.5 Anaerobes - Preferred regimen (1): Ciprofloxacin 0.3% ophthalmic ointment q15min for 6 hours then q30min for the remainder of day 1 then q1h on day 2, then q4h on days 3-14 - Preferred regimen (2): Ofloxacin 0.3% ophthalmic ointment q2h for 2-3 weeks - Preferred regimen (3): Levofloxacin 1.5% ophthalmic ointment q2h for 2-3 weeks ### Fungal (mycotic) Keratitis - 1. Causative Pathogens. - Candida spp. - Fusarium spp. - Aspergillus spp. - Curvularia spp. - 2. Empiric antimicrobial therapy - Preferred regimen (1): Natamycin 5% ophthalmic suspension q30min to q1h for 2-3 weeks - Preferred regimen (2): Fluconazole 1% ophthalmic suspension q1h for 2-3 weeks - Preferred regimen (3): Natamycin 5% ophthalmic suspension q30min to q1h for 2-3 weeks AND Fluconazole 1% ophthalmic suspension q1h for 2-3 weeks - Alternative regimen (1), unresponsive: Amphotericin B 0.15-0.25% prepared in distilled water q15min-q30min on day 1-2 then q1h to q2h for 2-3 weeks - Alternative regimen (2), unresponsive: Natamycin 5% ophthalmic suspension q30min to q1h for 2-3 weeks AND Amphotericin B 0.15-0.25% prepared in distilled water q15min-q30min on day 1-2 then q1h to q2h for 2-3 weeks - 3. Special considerations - Immunocompromised status, spreading ulcer, impending perforation, true perforation - Preferred regimen (1): Natamycin 5% ophthalmic suspension q30min to q1h for 2-3 weeks AND Fluconazole 1% ophthalmic suspension q1h for 2-3 weeks AND (Ketoconazole IV 200-400 mg q12h for 2-3 weeks OR Fluconazole IV 200 mg q12h for 2-3 weeks - Preferred regimen (2): Natamycin 5% ophthalmic suspension q30min to q1h for 2-3 weeks AND Amphotericin B 0.15-0.25% prepared in distilled water q15min-q30min on day 1-2 then q1h to q2h for 2-3 weeks AND (Ketoconazole IV 200-400 mg q12h for 2-3 weeks OR Fluconazole IV 200 mg q12h for 2-3 weeks - Note: Bacterial superinfection must be treated using Ciprofloxacin 0.3% ophthalmic ointment q15min for 6 hours then q30min for the remainder of day 1 then q1h on day 2, then q4h on days 3-14 OR (Cefazolin 5% q30min to q1h on day 1 then q1h on day 2 then q4h on days 3-14 AND Tobramycin 5% ophthalmic ointment q1h on day 1 then q2h on day 2 then q4h on days 3-14) ### Protozoal Keratitis - 1. Causative pathogens - Acanthamoeba spp. - Microsporidia spp. - 2. Empiric antimicrobial therapy - Preferred regimen (1): Polyhexamethylene biguanide 0.02% ophthalmic ointment q1h for 1-2 weeks AND Chlorhexidine 0.02% ophthalmic ointment q1h for 1-2 weeks AND/OR (Propamidine 0.1% ophthalmic ointment q1h for 1-2 weeks OR Hexamidine 0.1% ophthalmic ointment q1h for 2 days then q1h for another 3 days) - Preferred regimen (2): Propamidine 0.1% ophthalmic ointment q1h for 1-2 weeks AND Polyhexamethylene biguanide 0.02% ophthalmic ointment q1h for 1-2 weeks - Preferred regimen (4): Propamidine ophthalmic ointment q1h for 1-2 weeks AND Chlorhexidine ophthalmic ointment q1h for 1-2 weeks - Preferred regimen (4): Polyhexamethylene biguanide 0.02% ophthalmic ointment q1h for 1-2 weeks AND Hexamidine 0.1% ophthalmic ointment q1h for 2 days then q1h for another 3 days ### Viral Keratitis - 1. Causative pathogens - Herpes simplex virus (HSV) - 2. Empiric antimicrobial therapy - Preferred regimen (1): Acyclovir 3% ophthalmic ointment q5h for 2-3 weeks AND Homatropine 2% ophthalmic solution bid for 2-3 weeks - Preferred regimen (2): Idoxuridine 0.1% ophthalmic solution q1h in daytime and 0.5% ophthalmic ointment qhs for 1 week then 0.1% ophthalmic solution q2h in daytime and 0.5% ophthalmic ointment qhs for 2-3 weeks AND Homatropine 2% ophthalmic solution bid for 2-3 weeks ### Contraindicated medications Epithelial herpes simplex keratitis is considered an absolute contraindication to the use of the following medications: - Fluorometholone - Loteprednol - Rimexolone - Suprofen

Thrombin Thrombin (EC 3.4.21.5, fibrinogenase, thrombase, thrombofort, topical, thrombin-C, tropostasin, activated blood-coagulation factor II, blood-coagulation factor IIa, factor IIa, E thrombin, beta-thrombin, gamma-thrombin) is a serine protease, an enzyme that, in humans, is encoded by the F2 gene. Prothrombin (coagulation factor II) is proteolytically cleaved to form thrombin in the clotting process. Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions. # History After the description of fibrinogen and fibrin, Alexander Schmidt hypothesised the existence of an enzyme that converts fibrinogen into fibrin in 1872. # Physiology ## Synthesis Thrombin is produced by the enzymatic cleavage of two sites on prothrombin by activated Factor X (Xa). The activity of factor Xa is greatly enhanced by binding to activated Factor V (Va), termed the prothrombinase complex. Prothrombin is produced in the liver and is co-translationally modified in a vitamin K-dependent reaction that converts 10-12 glutamic acids in the N terminus of the molecule to gamma-carboxyglutamic acid (Gla). In the presence of calcium, the Gla residues promote the binding of prothrombin to phospholipid bilayers. Deficiency of vitamin K or administration of the anticoagulant warfarin inhibits the production of gamma-carboxyglutamic acid residues, slowing the activation of the coagulation cascade. In human adults, the normal blood level of antithrombin activity has been measured to be around 1.1 units/mL. Newborn levels of thrombin steadily increase after birth to reach normal adult levels, from a level of around 0.5 units/mL 1 day after birth, to a level of around 0.9 units/mL after 6 months of life. ## Mechanism of action In the blood coagulation pathway, thrombin acts to convert factor XI to XIa, VIII to VIIIa, V to Va, fibrinogen to fibrin, and XIII to XIIIa. Factor XIIIa is a transglutaminase that catalyzes the formation of covalent bonds between lysine and glutamine residues in fibrin. The covalent bonds increase the stability of the fibrin clot. Thrombin interacts with thrombomodulin. As part of its activity in the coagulation cascade, thrombin also promotes platelet activation and aggregation via activation of protease-activated receptors on the cell membrane of the platelet. ## Negative feedback Thrombin bound to thrombomodulin activates protein C, an inhibitor of the coagulation cascade. The activation of protein C is greatly enhanced following the binding of thrombin to thrombomodulin, an integral membrane protein expressed by endothelial cells. Activated protein C inactivates factors Va and VIIIa. Binding of activated protein C to protein S leads to a modest increase in its activity. Thrombin is also inactivated by antithrombin, a serine protease inhibitor. # Structure The molecular weight of prothrombin is approximately 72,000 Da. The catalytic domain is released from prothrombin fragment 1.2 to create the active enzyme thrombin, which has a molecular weight of 36,000 Da. Structurally, it is a member of the large PA clan of proteases. Prothrombin is composed of four domains; an N-terminal Gla domain, two kringle domains and a C-terminal trypsin-like serine protease domain. Factor Xa with factor V as a cofactor leads to cleavage of the Gla and two Kringle domains (forming together a fragment called fragment 1.2) and leave thrombin, consisting solely of the serine protease domain. As is the case for all serine proteases, prothrombin is converted to active thrombin by proteolysis of an internal peptide bond, exposing a new N-terminal Ile-NH3. The historic model of activation of serine proteases involves insertion of this newly formed N-terminus of the heavy chain into the β-barrel promoting the correct conformation of the catalytic residues. Contrary to crystal structures of active thrombin, hydrogen-deuterium exchange mass spectrometry studies indicate that this N-terminal Ile-NH3 does not become inserted into the β-barrel in the apo form of thrombin. However, binding of the active fragment of thrombomodulin appears to allosterically promote the active conformation of thrombin by inserting this N-terminal region. # Gene The thrombin (prothrombin) gene is located on the eleventh chromosome (11p11-q12). There are an estimated 30 people in the world that have been diagnosed with the congenital form of Factor II deficiency, which should not be confused with the prothrombin G20210A mutation, which is also called the factor II mutation. Prothrombin G20210A is congenital. Prothrombin G20210A is not usually accompanied by other factor mutations (i.e., the most common is factor V Leiden). The gene may be inherited heterozygous (1 pair), or much more rarely, homozygous (2 pairs), and is not related to gender or blood type. Homozygous mutations increase the risk of thrombosis more than heterozygous mutations, but the relative increased risk is not well documented. Other potential risks for thrombosis, such as oral contraceptives may be additive. The previously reported relationship of inflammatory bowel disease (i.e., Crohn's disease or ulcerative colitis) and prothrombin G20210A or factor V Leiden mutation have been contradicted by research. # Role in disease Activation of prothrombin is crucial in physiological and pathological coagulation. Various rare diseases involving prothrombin have been described (e.g., hypoprothrombinemia). Anti-prothrombin antibodies in autoimmune disease may be a factor in the formation of the lupus anticoagulant also known as (antiphospholipid syndrome). Hyperprothrombinemia can be caused by the G20210A mutation. Thrombin, a potent vasoconstrictor and mitogen, is implicated as a major factor in vasospasm following subarachnoid hemorrhage. Blood from a ruptured cerebral aneurysm clots around a cerebral artery, releasing thrombin. This can induce an acute and prolonged narrowing of the blood vessel, potentially resulting in cerebral ischemia and infarction (stroke). Beyond its key role in the dynamic process of thrombus formation, thrombin has a pronounced pro-inflammatory character, which may influence the onset and progression of atherosclerosis. Acting via its specific cell membrane receptors (protease activated receptors: PAR-1, PAR-3 and PAR-4), which are abundantly expressed in all arterial vessel wall constituents, thrombin has the potential to exert pro-atherogenic actions such as inflammation, leukocyte recruitment into the atherosclerotic plaque, enhanced oxidative stress, migration and proliferation of vascular smooth muscle cells, apoptosis and angiogenesis. Thrombin is implicated in the physiology of blood clots. Its presence indicates the existence of a clot. In 2013 a system for detecting the presence of thrombin was developed in mice. It combines peptide-coated iron oxide attached to "reporter chemicals". When a peptide binds to a thrombin molecule, the report is released and appears in the urine where it can be detected. Human testing has not been conducted. # Applications ## Research tool Due to its high proteolytic specificity, thrombin is a valuable biochemical tool. The thrombin cleavage site (Leu-Val-Pro-Arg-Gly-Ser) is commonly included in linker regions of recombinant fusion protein constructs. Following purification of the fusion protein, thrombin can be used to selectively cleave between the Arginine and Glycine residues of the cleavage site, effectively removing the purification tag from the protein of interest with a high degree of specificity. ## Medicine and surgery Prothrombin complex concentrate and fresh frozen plasma are prothrombin-rich coagulation factor preparations that can be used to correct deficiencies (usually due to medication) of prothrombin. Indications include intractable bleeding due to warfarin. Manipulation of prothrombin is central to the mode of action of most anticoagulants. Warfarin and related drugs inhibit vitamin K-dependent carboxylation of several coagulation factors, including prothrombin. Heparin increases the affinity of antithrombin to thrombin (as well as factor Xa). The direct thrombin inhibitors, a newer class of medication, directly inhibit thrombin by binding to its active site. Recombinant thrombin is available as a powder for reconstitution into aqueous solution. It can be applied topically during surgery, as an aid to hemostasis. It can be useful for controlling minor bleeding from capillaries and small venules, but ineffective and not indicated for massive or brisk arterial bleeding. ## Food production Thrombin is sold under the brand name Fibrimex for use as a binding agent for meat. The thrombin in Fibrimex derives from porcine or bovine blood. According to the manufacturer it can be used to produce new kinds of mixed meats (for example combining beef and fish seamlessly). The manufacturer also states that it can be used to combine whole muscle meat, form and portion these thus cutting down on production costs without a loss in quality. General secretary Jan Bertoft of Swedish Consumers' Association has stated that "there is danger of misleading the consumers since there is no way to tell this reconstituted meat from real meat"

ST14 Suppressor of tumorigenicity 14 protein, also known as matriptase, is a protein that in humans is encoded by the ST14 gene. ST14 orthologs have been identified in most mammals for which complete genome data are available. # Function Matriptase is an epithelial-derived, integral membrane serine protease. This protease forms a complex with the Kunitz-type serine protease inhibitor, HAI-1, and is found to be activated by sphingosine-1-phosphate. This protease has been shown to cleave and activate hepatocyte growth factor/scatter factor, and urokinase plasminogen activator, which suggest the function of this protease as an epithelial membrane activator for other proteases and latent growth factors. Matriptase is a type II transmembrane serine protease expressed in most human epithelia, where it is coexpressed with its cognate transmembrane inhibitor, hepatocyte growth factor activator inhibitor (HAI)-1. Activation of the matriptase zymogen requires sequential N-terminal cleavage, activation site autocleavage, and transient association with HAI-1. Matriptase has an essential physiological role in profilaggrin processing, corneocyte maturation, and lipid matrix formation associated with terminal differentiation of the oral epithelium and the epidermis, and is also critical for hair follicle growth. Matriptase is an 80- to 90-kDa cell surface glycoprotein with a complex modular structure that is common to all matriptases. # Clinical significance The expression of this protease has been associated with breast, colon, prostate, and ovarian tumors, which implicates its role in cancer invasion, and metastasis. Matriptase and HAI expression are frequently dysregulated in human cancer, and matriptase expression that is unopposed by HAI-1 potently promotes carcinogenesis and metastatic dissemination in animal models.

RBM39 RNA-binding protein 39 is a protein that in humans is encoded by the RBM39 gene. # Function The protein encoded by this gene is an RNA binding protein and possible splicing factor. The encoded protein is found in the nucleus, where it colocalizes with core spliceosomal proteins. Studies of a mouse protein with high sequence similarity to this protein suggest that this protein may act as a transcriptional coactivator for JUN/AP-1 and estrogen receptors. Multiple transcript variants encoding different isoforms have been observed for this gene. # Interactions RBM39 has been shown to interact with Estrogen receptor alpha, Estrogen receptor beta and C-jun.

Plexus Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview A plexus is a network. It has more specific meanings in multiple fields. # Biology In biology, plexus has multiple meanings. ## Nervous system In many animals the processes of neurons join together to form a plexus or nerve net. This is the characteristic form of nervous system in the coelenterates and persists with modifications in the flatworms. The nerves of the radially symmetric echinoderms also take this form, where a plexus underlies the ectoderm of these animals and, deeper in the body, other nerve cells form plexuses of limited extent. In vertebrates nerves branch and rejoin in some parts of the body, for example the brachial plexus made up of the spinal nerves which enter the arm and the solar plexus above the stomach. Almost a hundred such plexuses have been named in the human body, but the four primary nerve plexuses are the cervical plexus, brachial plexus, lumbar plexus, and the sacral plexus. ## Circulatory system A plexus is also a network of blood vessels, with the choroid plexuses of the brain being the most commonly mentioned example. Choroid plexuses are very thin and vascular roof plates of the most anterior and most posterior cavities of the brain which expand into the interiors of the cavities. Other vascular plexuses are found elsewhere in the body. de:Plexus (Medizin)

Immunoglobulin supergene family The immunoglobulin supergene family is "the group of proteins that have immunoglobulin-like domains, including histocompatibility antigens, the T-cell antigen receptor, poly-IgR, and other proteins involved in the vertebrate immune response (17)." # Immunoglobulin supergenes Each family within the immunoglobulin supergene family has its share of human genes: - ATP-binding cassette (ABC) transporters : 23, 6890, 6891, - Carcinoembryonic antigen genes : 634, 1048, 1084, 1087, 1088, 1089, 4680, 56971, 90273, 125931, 388551, 729767, - Cell adhesion molecule genes : 214, 914, 1826, 3897, 4059, 4162, 4684, 4685, 4897, 4978, 5175, 7412, 8174, 10752, 23705, 51148, 57453, 57863, 90952, 199731, 220296, 221935, 253559, - Cell adhesion-related genes : 50937, - Immunoglobulin domain genes : 915, 916, 917, 3492, 3493, 3494, 3495, 3496, 3497, 3500, 3501, 3502, 3503, 3507, 3514, 3515, 3519, 3535, 3537, 3538, 3539, 3543, 3546, 6405, 6696, 7075, 7842, 7869, 8217, 8482, 9037, 9723, 9860, 10371, 10500, 10501, 10505, 10507, 10509, 10512, 11317, 11326, 23584, 26018, 26103, 28299, 28385, 28386, 28388, 28389, 28391, 28392, 28394, 28395, 28396, 28397, 28398, 28399, 28400, 28401, 28406, 28408, 28409, 28410, 28412, 28414, 28420, 28423, 28424, 28426, 28434, 28439, 28442, 28444, 28445, 28448, 28449, 28450, 28451, 28452, 28454, 28455, 28457, 28458, 28461, 28464, 28465, 28466, 28467, 28468, 28472, 28473, 28474, 28475, 28476, 28477, 28479, 28481, 28483, 28484, 28485, 28486, 28487, 28488, 28490, 28491, 28492, 28494, 28496, 28497, 28498, 28499, 28500, 28501, 28502, 28503, 28504, 28505, 28506, 28507, 28509, 28510, 28772, 28773, 28774, 28775, 28776, 28778, 28779, 28781, 28782, 28783, 28784, 28785, 28786, 28791, 28793, 28795, 28796, 28797, 28799, 28802, 28803, 28804, 28809, 28813, 28814, 28815, 28816, 28817, 28820, 28822, 28823, 28825, 28826, 28827, 28828, 28831, 28832, 28833, 28834, 28874, 28875, 28876, 28877, 28878, 28881, 28882, 28883, 28891, 28893, 28896, 28900, 28901, 28902, 28903, 28904, 28907, 28908, 28912, 28913, 28914, 28916, 28919, 28921, 28923, 28930, 28933, 28935, 28937, 28938, 28939, 28940, 28941, 28942, 28943, 28946, 28947, 28948, 28949, 28950, 50802, 54437, 54841, 54910, 56920, 57289, 57290, 57556, 57715, 59307, 64218, 79037, 80031, 89770, 126259, 158038, 223117, 339398, 340745, 345193, - Immunoglobulin like domain smart00410 : 176, 558, 925, 926, 2260, 2261, 3570, 3791, 3815, 4916, 5133, 91937, 388364, 391123, - Immunoglobulin like domain pfam13895 : 942, 962, 2324, 3339, - Immunoglobulin like domain cd05751 : 9437, 10859, 11006, 11024, 11025, 11026, 51206, 79168, 353514, 102725035, 107987425, 107987462, - Immunoglobulin domain cl11960 : 920, 930, 2263, 2321, 3084, 5156, 5159, 7273, 29126, - Immunoglobulin receptor superfamily : 973, 974, 1630, 2208, 2209, 2212, 2213, 2214, 3802, 3803, 3804, 3805, 3806, 3808, 3809, 3810, 3811, 3812, 3813, 3903, 3904, 5284, 10288, 10990, 11027, 23547, 26762, 57292, 79368, 83416, 83417, 84868, 115350, 115352, 115653, 126014, 286676, 343413, 391123, 553128, 100132285, - Immunoglobulin superfamily genes : 682, 2204, 3321, 3476, 3547, 3671, 9398, 9543, 10261, 10871, 11314, 22997, 57549, 57611, 57722, 65978, 83953, 84966, 93185, 117166, 121227, 124857, 140885, 146722, 147710, 150084, 152404, 283284, 285313, 492311, - Immunoglobulin supergenes : 1, 7441, 29802, - Intercellular adhesion molecule genes : 3383, 3384, 3385, 3386, 7087, - Junction adhesion molecule genes : 50848, 58494, 83700, 120425, 340547, - Major histocompatibility complex class I gene family : 563, 567, 696, 821, 909, 910, 911, 912, 913, 2217, 2794, 3077, 3105, 3106, 3107, 3133, 3134, 3135, 3140, 4277, 6992, 7726, 10107, 10384, 10385, 11118, 11119, 11120, 79692, 222698, 282890, 353219, 100507436, - Major histocompatibility complex class II gene family : 972, 1302, 1388, 1616, 2968, 3108, 3109, 3111, 3112, 3113, 3115, 3117, 3118, 3119, 3120, 3121, 3122, 3123, 3125, 3126, 3127, 3833, 4261, 4904, 5089, 5252, 5696, 5698, 5863, 6015, 6046, 6048, 6222, 6257, 6293, 7922, 7923, 8705, 8831, 9277, 9278, 9374, 10471, - Major histocompatibility complex class III gene family : 177, 578, 629, 717, 720, 721, 780, 1041, 1192, 1432, 1460, 1589, 1797, 2289, 2914, 4295, 4439, 4736, 4758, 4855, 5460, 5514, 5603, 6204, 6631, 6732, 6882, 6941, 6954, 7148, 7287, 7407, 7629, 7936, 7940, 8449, 8859, 8870, 9656, 10211, 259197, - Major histocompatibility complex class IV gene family : 199, 3303, 3304, 3305, 3309, 6892, 23640, - Major histocompatibility complex class V gene family : 534, 7916, 7917, 7918, 7919, 7920, - Major histocompatibility complex class VI gene family : 4049, 4050, 7124, - ZAS family : 3096, - for a total of 517 genes. The human gene sequence is 1, 23, 176, 177, 199, 214, 534, 558, 563, 567, 578, 629, 634, 682, 696, 717, 720, 721, 780, 821, 909, 910, 911, 912, 913, 914, 915, 916, 917, 920, 925, 926, 930, 942, 962, 972, 973, 974, 1041, 1048, 1084, 1087, 1088, 1089, 1192, 1302, 1388, 1432, 1460, 1589, 1616, 1630, 1797, 1826, 2204, 2208, 2209, 2212, 2213, 2214, 2217, 2260, 2261, 2263, 2289, 2321, 2324, 2794, 2914, 2968, 3077, 3084, 3096, 3105, 3106, 3107, 3108, 3109, 3111, 3112, 3113, 3115, 3117, 3118, 3119, 3120, 3121, 3122, 3123, 3125, 3126, 3127, 3133, 3134, 3135, 3140, 3303, 3304, 3305, 3309, 3321, 3339, 3383, 3384, 3385, 3386, 3476, 3492, 3493, 3494, 3495, 3496, 3497, 3500, 3501, 3502, 3503, 3507, 3514, 3515, 3519, 3535, 3537, 3538, 3539, 3543, 3546, 3547, 3570, 3671, 3791, 3802, 3803, 3804, 3805, 3806, 3808, 3809, 3810, 3811, 3812, 3813, 3815, 3833, 3897, 3903, 3904, 4049, 4050, 4059, 4162, 4261, 4277, 4295, 4439, 4680, 4684, 4685, 4736, 4758, 4855, 4897, 4904, 4916, 4978, 5089, 5133, 5156, 5159, 5175, 5252, 5284, 5460, 5514, 5603, 5696, 5698, 5863, 6015, 6046, 6048, 6204, 6222, 6257, 6293, 6405, 6631, 6696, 6732, 6882, 6890, 6891, 6892, 6941, 6954, 6992, 7075, 7087, 7124, 7148, 7273, 7287, 7407, 7412, 7441, 7629, 7726, 7842, 7869, 7916, 7917, 7918, 7919, 7920, 7922, 7923, 7936, 7940, 8174, 8217, 8449, 8482, 8705, 8831, 8859, 8870, 9037, 9277, 9278, 9374, 9398, 9437, 9543, 9656, 9723, 9860, 10107, 10211, 10261, 10288, 10371, 10384, 10385, 10471, 10500, 10501, 10505, 10507, 10509, 10512, 10752, 10859, 10871, 10990, 11006, 11024, 11025, 11026, 11027, 11118, 11119, 11120, 11314, 11317, 11326, 11314, 22997, 23547, 23584, 23640, 23705, 26018, 26103, 26762, 28299, 28385, 28386, 28388, 28389, 28391, 28392, 28394, 28395, 28396, 28397, 28398, 28399, 28400, 28401, 28406, 28408, 28409, 28410, 28412, 28414, 28420, 28423, 28424, 28426, 28434, 28439, 28442, 28444, 28445, 28448, 28449, 28450, 28451, 28452, 28454, 28455, 28457, 28458, 28461, 28464, 28465, 28466, 28467, 28468, 28472, 28473, 28474, 28475, 28476, 28477, 28479, 28481, 28483, 28484, 28485, 28486, 28487, 28488, 28490, 28491, 28492, 28494, 28496, 28497, 28498, 28499, 28500, 28501, 28502, 28503, 28504, 28505, 28506, 28507, 28509, 28510, 28772, 28773, 28774, 28775, 28776, 28778, 28779, 28781, 28782, 28783, 28784, 28785, 28786, 28791, 28793, 28795, 28796, 28797, 28799, 28802, 28803, 28804, 28809, 28813, 28814, 28815, 28816, 28817, 28820, 28822, 28823, 28825, 28826, 28827, 28828, 28831, 28832, 28833, 28834, 28874, 28875, 28876, 28877, 28878, 28881, 28882, 28883, 28891, 28893, 28896, 28900, 28901, 28902, 28903, 28904, 28907, 28908, 28912, 28913, 28914, 28916, 28919, 28921, 28923, 28930, 28933, 28935, 28937, 28938, 28939, 28940, 28941, 28942, 28943, 28946, 28947, 28948, 28949, 28950, 29126, 29802, 50802, 50848, 50937, 51148, 51206, 54437, 54910, 54841, 56920, 56971, 57289, 57290, 57292, 57453, 57549, 57556, 57611, 57715, 57722, 57863, 58494, 59307, 64218, 65978, 79037, 79168, 79368, 79692, 80031, 83416, 83417, 83700, 83953, 84868, 84966, 89770, 90273, 90952, 91937, 93185, 115350, 115352, 115653, 117166, 120425, 121227, 124857, 125931, 126014, 126259, 140885, 146722, 147710, 150084, 152404, 158038, 199731, 220296, 221935, 222698, 223117, 253559, 259197, 282890, 283284, 285313, 286676, 339398, 340547, 340745, 343413, 345193, 353219, 353514, 388364, 388551, 391123, 492311, 553128, 729767, 100132285, 100507436, 102725035, 107987425, 107987462. Gene ID: 1 A1BG alpha-1-B glycoprotein on 19q13.43: "The protein encoded by this gene is a plasma glycoprotein of unknown function. The protein shows sequence similarity to the variable regions of some immunoglobulin supergene family member proteins." - NP_570602.2 alpha-1B-glycoprotein precursor, Conserved Domains (4) summary: cd05751 Location: 401 → 493 Ig1_LILRB1_like; First immunoglobulin (Ig)-like domain found in Leukocyte Ig-like receptors (LILR)B1 (also known as LIR-1) and similar proteins, smart00410 Location: 218 → 280 IG_like; Immunoglobulin like, pfam13895 Location: 210 → 301 Ig_2; Immunoglobulin domain and cl11960 Location: 28 → 110 Ig; Immunoglobulin domain. A1BG contains the immunoglobulin domain: cl11960 and three immunoglobulin-like domains: pfam13895, cd05751 and smart00410. "Immunoglobulin (Ig) domain found in the Ig superfamily. The Ig superfamily is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. Members of this group are components of immunoglobulin, neuroglia, cell surface glycoproteins, such as, T-cell receptors, CD2, CD4, CD8, and membrane glycoproteins, such as, butyrophilin and chondroitin sulfate proteoglycan core protein. A predominant feature of most Ig domains is a disulfide bridge connecting the two beta-sheets with a tryptophan residue packed against the disulfide bond." "This domain contains immunoglobulin-like domains." "Ig1_LILR_KIR_like: domain similar to the first immunoglobulin (Ig)-like domain found in Leukocyte Ig-like receptors (LILRs) and Natural killer inhibitory receptors (KIRs). This group includes LILRB1 (or LIR-1), LILRA5 (or LIR9), an activating natural cytotoxicity receptor NKp46, the immune-type receptor glycoprotein VI (GPVI), and the IgA-specific receptor Fc-alphaRI (or CD89). LILRs are a family of immunoreceptors expressed on expressed on T and B cells, on monocytes, dendritic cells, and subgroups of natural killer (NK) cells. The human LILR family contains nine proteins (LILRA1-3,and 5, and LILRB1-5). From functional assays, and as the cytoplasmic domains of various LILRs, for example LILRB1 (LIR-1), LILRB2 (LIR-2), and LILRB3 (LIR-3) contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) it is thought that LIR proteins are inhibitory receptors. Of the eight LIR family proteins, only LIR-1 (LILRB1), and LIR-2 (LILRB2), show detectable binding to class I MHC molecules; ligands for the other members have yet to be determined. The extracellular portions of the different LIR proteins contain different numbers of Ig-like domains for example, four in the case of LILRB1 (LIR-1), and LILRB2 (LIR-2), and two in the case of LILRB4 (LIR-5). The activating natural cytotoxicity receptor NKp46 is expressed in natural killer cells, and is organized as an extracellular portion having two Ig-like extracellular domains, a transmembrane domain, and a small cytoplasmic portion. GPVI, which also contains two Ig-like domains, participates in the processes of collagen-mediated platelet activation and arterial thrombus formation. Fc-alphaRI is expressed on monocytes, eosinophils, neutrophils and macrophages; it mediates IgA-induced immune effector responses such as phagocytosis, antibody-dependent cell-mediated cytotoxicity and respiratory burst." "IG domains that cannot be classified into one of IGv1, IGc1, IGc2, IG." "𝛂1B-glycoprotein(𝛂1B) consists of a single polypeptide chain N-linked to four glucosamine oligosaccharides. The polypeptide has five intrachain disulfide bonds and contains 474 amino acid residues. 𝛂1B exhibits internal duplication and consists of five repeating structural domains, each containing about 95 amino acids and one disulfide bond. several domains of 𝛂1B, especially the third, show statistically significant homology to variable regions of certain immunoglobulin light and heavy chains. 𝛂1B exhibits sequence similarity to other members of the immunoglobulin supergene family such as the receptor for transepithelial transport of IgA and IgM and the secretory component of human IgA." "Some of the domains of 𝛂1B show significant homology to variable (V) and constant (C) regions of certain immunoglobulins. Likewise, there is statistically significant homology between 𝛂1B and the secretory component (SC) of human IgA (15) and also with the extracellular portion of the rabbit receptor for transepithelial transport of polymeric immunoglobulins (IgA and IgM). Mostov et al. (16) have called the later protein the poly-Ig receptor or poly-IgR and have shown that it is the precursor of SC." Gene ID: 7441 is VPREB1 V-set pre-B cell surrogate light chain 1 on 22q11.22: "The protein encoded by this gene belongs to the immunoglobulin superfamily and is expressed selectively at the early stages of B cell development, namely, in proB and early preB cells. This gene encodes the iota polypeptide chain that is associated with the Ig-mu chain to form a molecular complex which is expressed on the surface of pre-B cells. The complex is thought to regulate Ig gene rearrangements in the early steps of B-cell differentiation. Alternative splicing results in multiple transcript variants." - NP_001290438.1 immunoglobulin iota chain isoform 2: "Transcript Variant: This variant (2) uses an alternate splice site in the coding region and initiates translation at an alternate start codon, compared to variant 1. The encoded isoform (2) has a distinct N-terminus and is shorter than isoform 1." Conserved Domains summary: smart00410 Location: 25 → 115 IG_like; Immunoglobulin like and cl11960 Location: 29 → 117 Ig; Immunoglobulin domain. - NP_009059.1 immunoglobulin iota chain isoform 1 precursor: "Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1)." Conserved Domains summary: smart00410 Location: 26 → 116 IG_like; Immunoglobulin like and cl11960 Location: 30 → 118 Ig; Immunoglobulin domain. Gene ID: 29802 is VPREB3 V-set pre-B cell surrogate light chain 3 on 22q11.23; 22q11: "The protein encoded by this gene is the human ortholog of the mouse VpreB3 (8HS20) protein, is thought to be involved in B-cell maturation, and may play a role in assembly of the pre-B cell receptor (pre-BCR). While the role of this protein in B-cell development has not yet been elucidated, studies with the chicken ortholog of this protein have found that when overexpressed, this protein localizes to the endoplasmic reticulum. The mouse ortholog of this protein has been shown to associate with membrane mu heavy chains early in the course of pre-B cell receptor biosynthesis. Expression of this gene has been observed in some lymphomas." - NP_037510.1 pre-B lymphocyte protein 3 precursor, Conserved Domains summary: cl11960 Location: 30 → 122 Ig; Immunoglobulin domain. # Carcinoembryonic antigen gene family # Immunoglobulin superfamily genes # Major histocompatibility complex genes ## Class I ## Class II ## Class III ## Class IV Several "genes have been described that are encoded in the telomeric end of the Class III region and that appear to be involved in both global and specific inflammatory responses. Due to this commonality of function this gene-rich region was dubbed Class IV, and includes the TNF family, AIF1, and HSP70." The B144/LST1 protein is expressed in T cell, monocytic, and macrophage cell lines, and is also substantially expressed in both murine and human dendritic cells in culture." "The 1C7 gene is located immediately adjacent to the B144 gene. RNA for B144 and 1C7 are transcribed in convergent directions such that there is a slight overlap between the 3' ends of the two mRNAs. 1C7 also shows multiple splice forms with 9 forms of the human mRNA reported so far.(21) The major forms encode proteins containing a leader sequence, a probable trans-membrane segment, an external sequence including an immunoglobulin-like domain, and at least three alternative forms of the putative intracellular segment of the protein. One alternative splice modifies the structure of the immunoglobulin-like domain, changing it from a sequence more closely resembling those of the V regions of Ig molecules to one that is more similar to IgC2 regions. Of the three alternative putative intracellular domains, one encodes multiple proline repeats suggestive of SH3 binding domains." "The existence of the G1 gene was initially noted as a part of a screen of MHC cosmids for embedded genes. The G1 and AIF1 transcripts appear to be derived by alternative splicing from partially overlapping genomic templates. A third human interferon gamma-responsive transcript, IRT-1, has been noted that shares some internal sequences with both G1 and AIF1, but on the basis of the predicted open reading frame it shares only limited amino acid sequences with G1." Gene ID: 199 is AIF1 allograft inflammatory factor 1 on 6p21.33: "This gene encodes a protein that binds actin and calcium. This gene is induced by cytokines and interferon and may promote macrophage activation and growth of vascular smooth muscle cells and T-lymphocytes. Polymorphisms in this gene may be associated with systemic sclerosis. Alternative splicing results in multiple transcript variants, but the full-length and coding nature of some of these variants is not certain." - NP_001305899.1 allograft inflammatory factor 1 isoform 1: "Transcript Variant: This variant (4) uses an alternate splice site in the 5' region and initiates translation at a downstream start codon compared to variant 3. The encoded isoform (1) has a shorter N-terminus than isoform 3. Variants 1 and 4 encode the same isoform (1)." - NP_001614.3 allograft inflammatory factor 1 isoform 3: "Transcript Variant: This variant (3) encodes the longest isoform (3)." - NP_116573.1 allograft inflammatory factor 1 isoform 1: "Transcript Variant: This variant (1, also known as G1) differs in the 5' UTR, lacks a portion of the 5' coding region, and initiates translation at a downstream start codon compared to variant 3. The encoded isoform (1) has a shorter N-terminus than isoform 3. Variants 1 and 4 encode the same isoform (1)." "AIF-1 (allograft inflammatory factor-1) is a Ca2+ binding protein predominantly expressed by activated monocytes, originally identified in rat cardiac allografts with chronic rejection.(22) The human cDNA homologue is 86% identical to the rat (90% identical to the amino acid sequence) and was identified by reverse transcriptase-PCR of endomyocardial biopsy specimens from human heart transplants and in macrophage cell lines.(23)" Gene ID: 3303 is HSPA1A heat shock protein family A (Hsp70) member 1A on 6p21.33: "This intronless gene encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 family. In conjuction with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles. It is also involved in the ubiquitin-proteasome pathway through interaction with the AU-rich element RNA-binding protein 1. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which encode similar proteins." Gene ID: 3304 is HSPA1B heat shock protein family A (Hsp70) member 1B on 6p21.33: "This intronless gene encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 family. In conjuction with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles. It is also involved in the ubiquitin-proteasome pathway through interaction with the AU-rich element RNA-binding protein 1. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which encode similar proteins." Gene ID: 3305 is HSPA1L heat shock protein family A (Hsp70) member 1 like on 6p21.33: "This gene encodes a 70kDa heat shock protein. In conjunction with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which also encode isoforms of the 70kDa heat shock protein." Gene ID: 3309 is HSPA5 heat shock protein family A (Hsp70) member 5 on 9q33.3: "The protein encoded by this gene is a member of the heat shock protein 70 (HSP70) family. It is localized in the lumen of the endoplasmic reticulum (ER), and is involved in the folding and assembly of proteins in the ER. As this protein interacts with many ER proteins, it may play a key role in monitoring protein transport through the cell." - NP_005338.1 endoplasmic reticulum chaperone BiP precursor. Gene ID: 6892 is TAPBP TAP binding protein on 6p21.32: "This gene encodes a transmembrane glycoprotein which mediates interaction between newly assembled major histocompatibility complex (MHC) class I molecules and the transporter associated with antigen processing (TAP), which is required for the transport of antigenic peptides across the endoplasmic reticulum membrane. This interaction is essential for optimal peptide loading on the MHC class I molecule. Up to four complexes of MHC class I and this protein may be bound to a single TAP molecule. This protein contains a C-terminal double-lysine motif (KKKAE) known to maintain membrane proteins in the endoplasmic reticulum. This gene lies within the major histocompatibility complex on chromosome 6. Alternative splicing results in three transcript variants encoding different isoforms." - NP_003181.3 tapasin isoform 1 precursor: "Transcript Variant: This variant (1) represents the longest transcript and encodes isoform 1. Ig; Immunoglobulin domain" - NP_757345.2 tapasin isoform 2 precursor: "Transcript Variant: This variant (2) differs in the 3' coding region and 3' UTR, compared to variant 1. The encoded isoform (2) has a distinct C-terminus and is longer than isoform 1." - NP_757346.2 tapasin isoform 3 precursor: "Transcript Variant: This variant (3) lacks an alternate in-frame exon in the central coding region, compared to variant 1, resulting in an isoform (3) that is shorter than isoform 1." Gene ID: 23640 is HSPBP1 HSPA (Hsp70) binding protein 1 on 19q13.42. - NP_001123578.1 hsp70-binding protein 1 isoform 2: "Transcript Variant: This variant (2) differs in the 5' UTR, lacks a portion of the 5' coding region and initiates translation at a downstream start codon, compared to variant 3. Variants 1 and 2 encode the same isoform (2), which has a shorter N-terminus, compared to isoform 1." - NP_001284529.1 hsp70-binding protein 1 isoform 1: "Transcript Variant: This variant (3) encodes the longer isoform (1)." - NP_036399.3 hsp70-binding protein 1 isoform 2: "Transcript Variant: This variant (1) differs in the 5' UTR, lacks a portion of the 5' coding region and initiates translation at a downstream start codon, compared to variant 3. Variants 1 and 2 encode the same isoform (2), which has a shorter N-terminus, compared to isoform 1." ## Class V "Vacuolar ATPase is a multi-subunit protein complex that transports H+ ions. It functions in general to mediate acidification of cellular vacuoles, and consequently in receptor recycling, lysosome formation, and cellular pH control. centromeric to the BAT1 gene encode exons of a gene, ATP6G, homologous to the G subunit of the vacuolar H+ ATPase of a number of species.(26) The mRNA for this gene had two alternative splice forms, with the shorter form removing the presumptive translation initiation codon of the longer form and therefore removing an amino terminal region of high homology to other G subunits. The longer splice form was selectively expressed in some B and T cell lines as compared with myelomonocytic lines. Vacuolar ATPase subunit G is up-regulated in neutrophils exposed to non-pathogenic bacteria (Yeramilli and Weissman, unpublished). The ATPase is also up-regulated in neutrophils by GM-CSF or phorbol myristic acid. Up-regulation of the ATPase is one of the mechanisms that may delay apoptosis in activated neutrophils. However a specific role for the ATP6G in inflammation remains to be established by more specific means." Gene ID: 534 is ATP6V1G2 ATPase H+ transporting V1 subunit G2 on 6p21.33: "This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of intracellular compartments of eukaryotic cells. V-ATPase dependent acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c", and d. Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes or alternatively spliced transcript variants. This encoded protein is one of three V1 domain G subunit proteins. This gene had previous gene symbols of ATP6G and ATP6G2. Alternatively spliced transcript variants encoding different isoforms have been described. Read-through transcription also exists between this gene and the downstream DEAD (Asp-Glu-Ala-Asp) box polypeptide 39B (DDX39B) gene." - NP_001191007.1 V-type proton ATPase subunit G 2 isoform c. - NP_569730.1 V-type proton ATPase subunit G 2 isoform a. - NP_612139.1 V-type proton ATPase subunit G 2 isoform b. Gene ID: 7916 is PRRC2A proline rich coiled-coil 2A aka G2; BAT2; D6S51; D6S51E on 6p21.33: "A cluster of genes, BAT1-BAT5, has been localized in the vicinity of the genes for TNF alpha and TNF beta. These genes are all within the human major histocompatibility complex class III region. This gene has microsatellite repeats which are associated with the age-at-onset of insulin-dependent diabetes mellitus (IDDM) and possibly thought to be involved with the inflammatory process of pancreatic beta-cell destruction during the development of IDDM. This gene is also a candidate gene for the development of rheumatoid arthritis. Two transcript variants encoding the same protein have been found for this gene." - NP_004629.3 protein PRRC2A: "Transcript Variant: This variant (2) represents the longer transcript. Variants 1 and 2 both encode the same protein." - NP_542417.2 protein PRRC2A: "Transcript Variant: This variant (1) differs in the 5' UTR compared to variant 2. Variants 1 and 2 both encode the same protein." Gene ID: 7917 is BAG6 BAG cochaperone 6 aka G3; BAT3 on 6p21.33: "This gene was first characterized as part of a cluster of genes located within the human major histocompatibility complex class III region. This gene encodes a nuclear protein that is cleaved by caspase 3 and is implicated in the control of apoptosis. In addition, the protein forms a complex with E1A binding protein p300 and is required for the acetylation of p53 in response to DNA damage. Multiple transcript variants encoding different isoforms have been found for this gene." - NP_001092004.1 large proline-rich protein BAG6 isoform b: "Transcript Variant: This variant (4) differs in the 5' UTR and utilizes an alternative in-frame splice site in the 5' coding region, compared to variant 1. Variants 2, 3, and 4 encode the same isoform (b), which is 6 aa shorter than isoform a." - NP_001186626.1 large proline-rich protein BAG6 isoform c: "Transcript Variant: This variant (5) differs in the 5' UTR and lacks three alternate in-frame segments compared to variant 1. The resulting isoform (c) has the same N- and C-termini but is shorter compared to isoform a." - NP_001186627.1 large proline-rich protein BAG6 isoform d: "Transcript Variant: This variant (6) differs in the 5' UTR and lacks an alternate in-frame exon compared to variant 1. The resulting isoform (d) has the same N- and C-termini but is shorter compared to isoform a." - NP_542433.1 large proline-rich protein BAG6 isoform b: "Transcript Variant: This variant (2) differs in the 5' UTR and utilizes an alternative in-frame splice site in the 5' coding region, compared to variant 1. Variants 2, 3, and 4 encode the same isoform (b), which is 6 aa shorter than isoform a." - NP_542434.1 large proline-rich protein BAG6 isoform b: "Transcript Variant: This variant (3) utilizes an alternative in-frame splice site in the 5' coding region, compared to variant 1. Variants 2, 3, and 4 encode the same isoform (b), which is 6 aa shorter than isoform a." Gene ID: 7918 is GPANK1 G-patch domain and ankyrin repeats 1 aka G5; BAT4, on 6p21.33: "This gene is located in a cluster of HLA-B-associated transcripts, which is included in the human major histocompatability complex III region. This gene encodes a protein which is thought to play a role in immunity. Multiple alternatively spliced variants, encoding the same protein, have been identified." - NP_001186166.1 G patch domain and ankyrin repeat-containing protein 1: "Transcript Variant: This variant (1) represents the longest transcript." - NP_001186167.1 G patch domain and ankyrin repeat-containing protein 1: "Transcript Variant: This variant (3) differs in the 5' UTR compared to variant 1. Variants 1, 2, 3, 4, and 5 encode the same protein." - NP_001186168.1 G patch domain and ankyrin repeat-containing protein 1: "Transcript Variant: This variant (4) differs in the 5' UTR compared to variant 1. Variants 1, 2, 3, 4, and 5 encode the same protein." - NP_001186169.1 G patch domain and ankyrin repeat-containing protein 1: "Transcript Variant: This variant (5) differs in the 5' UTR compared to variant 1. Variants 1, 2, 3, 4, and 5 encode the same protein." - NP_149417.1 G patch domain and ankyrin repeat-containing protein 1: "Transcript Variant: This variant (2) differs in the 5' UTR compared to variant 1. Variants 1, 2, 3, 4, and 5 encode the same protein." Gene ID: 7919 is DDX39B DExD-box helicase 39B aka BAT1 on 6p21.33: "This gene encodes a member of the DEAD box family of RNA-dependent ATPases that mediate ATP hydrolysis during pre-mRNA splicing. The encoded protein is an essential splicing factor required for association of U2 small nuclear ribonucleoprotein with pre-mRNA, and it also plays an important role in mRNA export from the nucleus to the cytoplasm. This gene belongs to a cluster of genes localized in the vicinity of the genes encoding tumor necrosis factor alpha and tumor necrosis factor beta. These genes are all within the human major histocompatibility complex class III region. Mutations in this gene may be associated with rheumatoid arthritis. Alternative splicing results in multiple transcript variants. Related pseudogenes have been identified on both chromosomes 6 and 11. Read-through transcription also occurs between this gene and the upstream ATP6V1G2 (ATPase, H+ transporting, lysosomal 13kDa, V1 subunit G2) gene." - NP_004631.1 spliceosome RNA helicase DDX39B: "Transcript Variant: This variant (1) represents the longest transcript. Both variants 1 and 2 encode the same protein." - NP_542165.1 spliceosome RNA helicase DDX39B: "Transcript Variant: This variant (2) uses an alternative splice site in the 5' UTR, compared to variant 1. Both variants 1 and 2 encode the same protein." Gene ID: 7920 is ABHD16A abhydrolase domain containing 16A, phospholipase, aka BAT5 on 6p21.33: "A cluster of genes, BAT1-BAT5, has been localized in the vicinity of the genes for tumor necrosis factor alpha and tumor necrosis factor beta. These genes are all within the human major histocompatibility complex class III region. The protein encoded by this gene is thought to be involved in some aspects of immunity. Alternatively spliced transcript variants have been described." - NP_001170986.1 phosphatidylserine lipase ABHD16A isoform b: "Transcript Variant: This variant (2) differs in the 5' UTR and has multiple coding region differences, compared to variant 1. These differences cause translation initiation at an alternate AUG and result in an isoform (b) with a shorter, distinct N-terminus, compared to isoform 1." - NP_066983.1 phosphatidylserine lipase ABHD16A isoform a: "Transcript Variant: This variant (1) encodes the longer isoform (a)." ## Class VI "A cluster of genes for three related cytokines/cytokine receptors, tumor necrosis factor (TNF, formerly known as TNF-alpha or cachectin), lymphotoxin alpha (LTA), and lymphotoxin beta (LTB), lies in the Class IV region shortly before the most centromeric Class I related genes. TNF has been very extensively studied(5) and plays an important role in inflammation, bacterial(6) and viral infection,(7) tumor cachexia and the immune response. It is produced by a variety of cells including prominently monocytes, macrophages, and some T cell subsets." "LTB (also called TNF C) is a membrane bound molecule that forms a heterotrimer with LTA.(12) This LTA-LTB complex can then induce activation of NF kappa B in certain cell lines by binding with the LTB receptor, a member of the TNF receptor family.(13) (14) NF kappa B is a pleiotropic transcription factor capable of activating the expression of a great variety of genes critical for the Immunoin flammatory response.(14)" The region within the MHC class III gene cluster that contains genes for TNFs is also known as MHC class VI or the inflammatory region. Gene ID: 4049 is LTA lymphotoxin alpha on 6p21.33: "The encoded protein, a member of the tumor necrosis factor family, is a cytokine produced by lymphocytes. The protein is highly inducible, secreted, and forms heterotrimers with lymphotoxin-beta which anchor lymphotoxin-alpha to the cell surface. This protein also mediates a large variety of inflammatory, immunostimulatory, and antiviral responses, is involved in the formation of secondary lymphoid organs during development and plays a role in apoptosis. Genetic variations in this gene are associated with susceptibility to leprosy type 4, myocardial infarction, non-Hodgkin's lymphoma, and psoriatic arthritis. Alternatively spliced transcript variants have been observed for this gene." - NP_000586.2 lymphotoxin-alpha precursor: "Transcript Variant: This variant (2) differs in the 5' UTR compared to variant 1. Both variants 1 and 2 encode the same protein." - NP_001153212.1 lymphotoxin-alpha precursor: "Transcript Variant: This variant (1) represents the longer transcript. Both variants 1 and 2 encode the same protein." Gene ID: 4050 is LTB lymphotoxin beta on 6p21.33: "Lymphotoxin beta is a type II membrane protein of the TNF family. It anchors lymphotoxin-alpha to the cell surface through heterotrimer formation. The predominant form on the lymphocyte surface is the lymphotoxin-alpha 1/beta 2 complex (e.g. 1 molecule alpha/2 molecules beta) and this complex is the primary ligand for the lymphotoxin-beta receptor. The minor complex is lymphotoxin-alpha 2/beta 1. LTB is an inducer of the inflammatory response system and involved in normal development of lymphoid tissue. Lymphotoxin-beta isoform b is unable to complex with lymphotoxin-alpha suggesting a function for lymphotoxin-beta which is independent of lympyhotoxin-alpha. Alternative splicing results in multiple transcript variants encoding different isoforms." - NP_002332.1 lymphotoxin-beta isoform a: "Transcript Variant: This variant (1) represents the longer transcript, encodes the longer isoform (a), and can form the heterotrimeric complex with lymphotoxin-alpha." - NP_033666.1 lymphotoxin-beta isoform b: "Transcript Variant: This splice variant (2) lacks an exon in the coding region, compared to variant 1. The encoded protein (isoform b) has a premature stop codon and lacks the majority of the extracellular domain, compared to isoform a. This loss impairs its ability to complex with lympytoxin-alpha." Gene ID: 7124 is TNF tumor necrosis factor on 6p21.33: "This gene encodes a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF) superfamily. This cytokine is mainly secreted by macrophages. It can bind to, and thus functions through its receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. This cytokine is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. This cytokine has been implicated in a variety of diseases, including autoimmune diseases, insulin resistance, and cancer. Knockout studies in mice also suggested the neuroprotective function of this cytokine." ## ATP-binding cassette (ABC) transporters Gene ID: 23 is ABCF1 ATP binding cassette subfamily F member 1, on 6p21.33: "The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the GCN20 subfamily. Unlike other members of the superfamily, this protein lacks the transmembrane domains which are characteristic of most ABC transporters. This protein may be regulated by tumor necrosis factor-alpha and play a role in enhancement of protein synthesis and the inflammation process." No immunoglobulins. - NP_001020262.1 ATP-binding cassette sub-family F member 1 isoform a: "Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (a)." - NP_001081.1 ATP-binding cassette sub-family F member 1 isoform b: "Transcript Variant: This variant (2) lacks an alternate in-frame exon, compared to variant 1. The resulting protein (isoform b) is shorter than isoform a." Gene ID: 6890 is TAP1 transporter 1, ATP binding cassette subfamily B member aka transporter, ATP-binding cassette, major histocompatibility complex, 1 on 6p21.32: "The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is involved in the pumping of degraded cytosolic peptides across the endoplasmic reticulum into the membrane-bound compartment where class I molecules assemble. Mutations in this gene may be associated with ankylosing spondylitis, insulin-dependent diabetes mellitus, and celiac disease. Two transcript variants encoding different isoforms have been found for this gene." No immunoglobulins. - NP_000584.3 antigen peptide transporter 1 isoform 1: "Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1)." - NP_001278951.1 antigen peptide transporter 1 isoform 2: "Transcript Variant: This variant (2) differs in the 5' UTR and coding sequence compared to variant 1. The resulting isoform (2) is shorter at the N-terminus compared to isoform 1." Gene ID: 6891 is TAP2 transporter 2, ATP binding cassette subfamily B member on 6p21.32: "The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. This gene is located 7 kb telomeric to gene family member ABCB2. The protein encoded by this gene is involved in antigen presentation. This protein forms a heterodimer with ABCB2 in order to transport peptides from the cytoplasm to the endoplasmic reticulum. Mutations in this gene may be associated with ankylosing spondylitis, insulin-dependent diabetes mellitus, and celiac disease. Alternative splicing of this gene produces products which differ in peptide selectivity and level of restoration of surface expression of MHC class I molecules." No immunoglobulins. - NP_000535.3 antigen peptide transporter 2 isoform 1: "Transcript Variant: This variant (1, B allele) represents the longer transcript and encodes the longest isoform (1). An allele (variant 1, A allele) exists in which a single nt change creates an internal stop codon, leading to a protein that is 17 aa shorter at the C-terminus." - NP_001276972.1 antigen peptide transporter 2 isoform 3: "Transcript Variant: This variant (1, A allele) differs at 3 nt positions compared to variant 1, B allele. The resulting isoform (3) is shorter at the C-terminus compared to isoform 1." - NP_061313.2 antigen peptide transporter 2 isoform 2: "Transcript Variant: This variant (2) differs in the 5' UTR and coding region compared to variant 1. The resulting isoform (2) is shorter and has a distinct C-terminus compared to isoform 1." ## Immunoglobulin domain genes ## Immunoglobulin receptor superfamily ## ZAS family Gene ID: 3096 is HIVEP1 HIVEP zinc finger 1 aka major histocompatibility complex binding protein 1 on 6p24.1: "This gene encodes a transcription factor belonging to the ZAS family, members of which are large proteins that contain a ZAS domain - a modular protein structure consisting of a pair of C2H2 zinc fingers with an acidic-rich region and a serine/threonine-rich sequence. These proteins bind specifically to the DNA sequence motif, GGGACTTTCC, found in the enhancer elements of several viral promoters, including human immunodeficiency virus (HIV), and to related sequences found in the enhancer elements of a number of cellular promoters. This protein binds to this sequence motif, suggesting a role in the transcriptional regulation of both viral and cellular genes." - NP_002105.3 zinc finger protein 40. # Hypotheses - Downstream core promoters may work as transcription factors even as their complements or inverses. - In addition to the DNA binding sequences listed above, the transcription factors that can open up and attach through the local epigenome need to be known and specified.

Spiral valves of Heister # Overview Spiral valves of Heister are undulating folds or valves in the proximal mucosa of the cystic duct. The cystic duct attaches the gallbladder to the common bile duct. The spiral valves of Heister are supported by underlying smooth muscle fibers. There is some uncertainty regarding the role of the folds. Historically, physicians believed that their function was to aid in the passage of bile to and from the gallbladder, as well as regulate the degree of gallbladder distension. The presence of the spiral folds, in combination with the tortuosity of the cystic duct, makes endoscopic cannulation and catheterization of the cystic duct extremely difficult. Also, the valves of Heister impede the introduction of surgical instruments and are susceptible to lacerations. They were named after German anatomist Lorenz Heister (1683-1758).

Immunological Outcomes of New Tuberculosis Vaccine Trials: WHO Panel Recommendations [bib_ref] Immunology of tuberculosis and implications in vaccine development, Flynn [/bib_ref] [bib_ref] Exploiting immunology and molecular genetics for rational vaccine design against tuberculosis, Kaufmann [/bib_ref] [bib_ref] Immunology of tuberculosis and implications in vaccine development, Flynn [/bib_ref] [bib_ref] Exploiting immunology and molecular genetics for rational vaccine design against tuberculosis, Kaufmann [/bib_ref] [bib_ref] Tuberculosis vaccines: Past, present and future, Martin [/bib_ref] [bib_ref] Advances in tuberculosis vaccine strategies, Skeiky [/bib_ref] ## T cell assays that may be used in new tb vaccine trials Some T cell assays use whole blood, while others use isolated peripheral blood mononuclear cells (PBMCs). PBMCs may either be used fresh, or after cryopreservation. Assays may have relatively short (less than 24 hours), intermediate (one to three days), or longer (five to seven days) periods of incubation. Each assay approach may have distinct advantages, as summarised in [fig_ref] Table S1: German translation of the abstract by UJF Found at doi [/fig_ref]. The choice of assay system may be guided by the aspect of T cell immunity to be measured; for example, as described in [fig_ref] Table S1: German translation of the abstract by UJF Found at doi [/fig_ref] , longer-term assays may be better for measuring central memory T cell responses thought to be critical for long-term protection induced by vaccines [bib_ref] CD8 T cell detection of bacterial infection: Sniffing for formyl peptides derived..., Lauvau [/bib_ref] [bib_ref] HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is..., Migueles [/bib_ref] [bib_ref] Two subsets of memory T lymphocytes with distinct homing potentials and effector..., Sallusto [/bib_ref] Research sponsored three meetings of experts to discuss assay harmonization for new tuberculosis vaccine trials. assay approaches and make specific recommendations for phase I/IIa trials. These include introducing a single and simple harmonised assay for all trials. often dictated by what is practical in the setting; for example, if incubation of whole blood or PBMC isolation early after blood collection cannot be accomplished readily, it may be wiser to perform longer-term diluted whole-blood or PBMC assays, to minimise a potentially significant effect of processing delay on assay outcome (see below). Blood volume restrictions in infants, compared with adults, may further dictate assay choice (see below). T cell assays that are widely used and that appear practical in phase I/IIa trials include five to seven-day whole-blood or PBMC assays of cytokine production and proliferation, overnight or 48-hour enzyme-linked immunosorbent spot (ELISPOT) assays (see protocol in Text S1), and intracellular cytokine assays after six to 18-hour incubation of whole blood or PBMC with specific antigens (see protocol in Text S2). A discussion of these assays, including specific advantages and disadvantages of each and experience in TB vaccinology, may be found in Text S3. Text S3 also includes a discussion of less frequently used assays, such as cytotoxic cell degranulation assays, mycobacterial inhibition assays, and tetramer assays. At this stage, comparisons of assay outcomes among different new TB vaccine trials are not possible, mainly due to the diversity of technical approaches, even if the same basic assay system is used. ## Time to incubation of whole blood, or to pbmc isolation Delaying incubation of whole blood, or delaying isolation of PBMCs after blood collection, may affect assay outcomes (see Text S3 for more detail). Overall, available evidence suggests that sub-optimal outcomes of shorter-term assays are likely when delays occur from the time of blood collection to incubation, or to PBMC isolation and cryopreservation for later incubation. The panel therefore recommended that until further evidence becomes available, PBMCs for later ELISPOT and short-term intracellular cytokine assays be isolated as soon as possible after blood collection and never more than eight hours after collection, preferably at the same time point after collection in all participants of a specific study. The same principles apply to short-term, undiluted whole-blood intracellular cytokine assays; incubation later than two hours after collection should not be considered. In contrast, longer-term assays, such as a six to seven-day wholeblood assay, appear to be less affected by delays in incubation (H. M. Dockrell, personal communication); we hypothesise that these assays measure expansion of specific T cells, and are therefore less affected than shorter-term assays that measure direct ex vivo function quantitatively. ## Recent advances in pbmc cryopreservation and thawing Multiple variables in the PBMC isolation, cryopreservation, and thawing process affect ultimate recovery of viable, functional cells [bib_ref] Maximizing the retention of antigen specific lymphocyte function after cryopreservation, Disis [/bib_ref] ; Smith and Dockrell, unpublished data). Although most labs use very similar procedures, conflicting results regarding fine details such as freezing media composition have emerged (T. Kollmann, personal communication; [bib_ref] Maximizing the retention of antigen specific lymphocyte function after cryopreservation, Disis [/bib_ref]. However, most researchers now agree that assay results of increased quality may be obtained when PBMCs are "rested" for at least four hours after thawing, prior to adding antigens for functional assays. In shorter-term assays, this procedure may decrease assay background and increase functional response [bib_ref] Optimization and validation of an 8-color intracellular cytokine staining (ICS) assay to..., Horton [/bib_ref] [bib_ref] Impact of cryopreservation on tetramer, cytokine flow cytometry, and ELISPOT, Maecker [/bib_ref]. ## Harmonisation, standardisation, and validation of assays "Harmonisation" refers to a consensus in assay standard operating procedures for multiple testing sites. "Standardisation" comprises all measures necessary to obtain comparable results, in terms of both time and place. Optimal standardisation will result in comparable results when a test is performed at different times and by different technicians in different laboratories. To achieve such results, standardised materials, reagents, and equipment are important. "Validation" refers to a detailed characterisation of assay performance. Typical validation characteristics include accuracy, repeatability, specificity, detection limit, quantitation limit, linearity, and range. Regulatory authorities require that investigators introduce a validated assay as the primary immunological outcome in new vaccine trials, if the data are intended to be used for licensure. "Qualification" is a term sometimes used to describe partial validation, and refers to an experimental protocol that demonstrates that an accepted method will provide meaningful data, given specific conditions and samples. Currently, a number of different harmonised standard operating procedures have been prepared within different multi-national consortia or projects such as the European ## Union-supported tb-vac and muvapred (mucosal vaccines for poverty related diseases) initiatives, bill & melinda gates foundation grand challenges in global Health projects such as GC6-74 ("Biomarkers for TB"), and EUROVAC. All the assays discussed here are used to some extent by these large consortia, and in some cases the differences between protocols are relatively minor. It should therefore be relatively simple to get stakeholders together and produce harmonised protocols, particularly as small differences in protocols may make a major difference in the outcome of certain assays such as the ELISPOT. The panel therefore recommended that efforts at harmonisation and standardisation of assays should be supported. We recommend starting the discussion process with harmonisation and standardisation of the short-term ELISPOT assay and the longer-term whole-blood interferon (IFN)-γ assay. Further, standardisation of positive controls and detection methods should be attempted. (See Text S3 for more information.) ## A single, common assay in new vaccine trials It is likely that investigators and sponsors will continue to introduce their "favourite" assays in new TB vaccine trials. However, a single, harmonised assay common to all vaccine trials would be ideal to allow comparison of immunogenicity results between different vaccine candidates, and the use of such an assay is strongly recommended by members of this expert panel. Ideally, such an assay should be widely implementable, even at remote field sites, while delivering informative results. The panel judged that the seven-day wholeblood IFN-γ assay best meets these criteria and recommended that it be introduced into all new TB vaccine trials. Excellent performance of this assay has been demonstrated in multiple large clinical studies. Additionally, GC6-74 ("Biomarkers for TB") has standardised this method to screen new TB antigens at field sites. A harmonised protocol has been developed (Text S4). It will also be important to standardise reagents and the equipment that measures cytokine levels. ## "vaccine take" and immune correlates/surrogates of protection against tb All current assays described here use the magnitude and, to some extent, the qualitative character of the immune response to measure "vaccine take". Without a complete knowledge of immune correlates of vaccination-induced protection against TB, all assays may be described as vaccine take assays. Regardless, the current assays focus on T cell immunity, particularly IFN-γ production, which is thought to be important for protection. Because emerging evidence suggests that IFN-γ production alone is not necessarily an immune correlate of vaccination-induced protection against TB (W. A. Hanekom, unpublished observations; [bib_ref] Poor correlation between BCG vaccination-induced T cell responses and protection against tuberculosis, Mittrucker [/bib_ref] it is important to define these correlates in complementary projects. Multiple ongoing projects aim to define immune correlates of protection, which may ultimately be validated as surrogates of protection in phase IIb/III trials of effective TB vaccines. Until these correlates/surrogates are available, it would be extremely useful to also store blood products in a manner that is efficient and that would allow an excellent functional yield of cells or products when thawed at a later stage. These blood products would then be available to measure newly described immune correlates/surrogates of protection, in retrospective studies or for application of newer technologies. The panel therefore recommended that PBMCs should be stored for possible future use in new TB vaccine trials. Various protocols for PBMC isolation, cryopreservation, and thawing are available [bib_ref] Maximizing the retention of antigen specific lymphocyte function after cryopreservation, Disis [/bib_ref] [bib_ref] Impact of cryopreservation on tetramer, cytokine flow cytometry, and ELISPOT, Maecker [/bib_ref]. It should be noted that the shortest possible interval from blood collection until cryopreservation is desirable (see above), but because this may not be practical, it may be best to standardise the time from blood collection to PBMC isolation. ## Supporting information Alternative Language Abstract S1. PBMCs should be collected and stored, for later assessment of whether biomarkers of vaccination-induced protection against tuberculosis that are described are indeed induced by the vaccine, or when critical comparative questions need to be resolved. Harmonisation and standardisation of these assays, across vaccination sites, should be promoted. combination of both shorter-term and longer-term assays would be optimal to measure vaccination-induced immunity, be these PBMC or whole blood-based. The choice of specific assays should be left to individual investigators; it was noted that all current vaccine trials already use a combination of shorter-term and longer-term assays. single and simple harmonised assay should be introduced in all trials. [table] Table S1: German translation of the abstract by UJF Found at doi:10.1371/journal.pmed.0050145.sd001 (25 KB DOC). Alternative Language Abstract S2. French translation of the abstract by UJF Found at doi:10.1371/journal.pmed.0050145.sd002 (25 KB DOC). Alternative Language Abstract S3. Spanish translation of the abstract by UJF Found at doi:10.1371/journal.pmed.0050145.sd003 (25 KB DOC). The advantages and disadvantages of different assay approaches for delineating T cell immunity Found at doi:10.1371/journal.pmed.0050145.st001 (37 KB DOC). Text S1. IFN-γ ELISPOT protocol Found at doi:10.1371/journal.pmed.0050145.sd004 (96 KB DOC). Text S2. A sample short-term whole-blood stimulation protocol Found at doi:10.1371/journal.pmed.0050145.sd005 (85 KB DOC). Text S3. A longer, more detailed version of this manuscript Found at doi:10.1371/journal.pmed.0050145.sd006 (272 KB DOC). Text S4. The protocol for the recommended "universal" assay Found at doi:10.1371/journal.pmed.0050145.sd007 (90 KB DOC). Box 1. Recommendations of the Panel Regarding Assay Selection for Tuberculosis Vaccine Trials time from blood collection to incubation or to PBMC isolation in assays. [/table]

Bile acid sequestrant # Overview The bile acid sequestrants are a group of medications used for binding certain components of bile in the gastrointestinal tract. They disrupt the enterohepatic circulation of bile acids by sequestering them and preventing their reabsorption from the gut. They are generally classified as hypolipidemic agents, although they may be used for purposes other than lowering cholesterol. # Mechanism of action Bile acid sequestrants are polymeric compounds which serve as ion exchange resins. Bile acid sequestrants exchange anions such as chloride ions for bile acids. By doing so, they bind bile acids and sequester them from enterohepatic circulation. Since bile acid sequestrants are large polymeric structures, they are not well-absorbed from the gut into the bloodstream. Thus, bile acid sequestrants, along with any bile acids bound to the drug, are excreted via the feces after passage through the gastrointestinal tract. # Indications Since bile acids are biosynthesized from cholesterol, the disruption of bile acid reabsorption will decrease cholesterol levels, particularly low density lipoprotein (commonly known as "bad cholesterol"). Therefore, they may be used for the treatment of hypercholesterolemia and dyslipidemia. In chronic liver diseases such as cirrhosis, bile acids may deposit in the skin, causing pruritus (itching). Hence, bile acid sequenstrants may be used for the prevention of pruritus in patients with chronic liver disease. Additionally, diarrhea may be caused by excess bile salts entering the colon rather than being absorbed at the end of the small intestine, typically shortly after eating. Bile salt diarrhea is a possible side-effect of gallbladder removal. Bile acid sequestrants may reduce diarrhea in these patients. # Examples of bile acid sequestrants Three drugs are members of this class; all are synthetic polymeric resins: - Cholestyramine (Questran) - Colesevelam (Cholestagel in Europe, WelcholTM in the USA) - Colestipol (Colestid) # Side effects Since bile acid sequestrants are designed to stay in the gut, they generally do not have systemic side effects. However, they may cause problems in the gastrointestinal tract (GI tract), such as constipation, diarrhea, and flatulence. Some patients complain of the bad taste. # Drug interactions In addition to bile acids, bile acid sequestrants may also bind drugs in the GI tract, preventing their absorption into the bloodstream. For this reason, it is generally advised that bile acid sequestrants be spaced several hours apart from other drugs. They may also bind fat-soluble vitamins, such as vitamin A, vitamin D, vitamin E, and vitamin K. This effect may result in a vitamin deficiency. Hence, vitamin supplementation may be warranted. # Role in clinical use Use of these agents as hypolipidemic agents has decreased markedly since the introduction of the statins, which are more efficacious than bile acid sequestrants at lowering LDL. They are occasionally used as an adjunct to the statins; this is because the fibrates (another major group of cholesterol-lowering drugs) are thought to increase the risk of rhabdomyolysis when used with statins, and so this otherwise expectable combination is frequently avoided. Additionally, because bile acid sequestrants are not well-absorbed from the gut, they are generally regarded as being safe in pregnant women. However, by interfering with vitamin absorption, they may cause vitamin deficiencies that may affect the fetus. Hence, vitamin supplementation may be warranted, with appropriate intervals between dosing of the vitamins and bile acid sequestrants.

Morbidity and Mortality Weekly Report depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction Epidemics of influenza typically occur during the winter months in temperate regions and have been responsible for an average of approximately 36,000 deaths/year in the United States during 1990-1999 (1). Influenza viruses also can cause pandemics, during which rates of illness and death from influenza-related complications can increase worldwide. Influenza viruses cause disease among all age groups (2)(3)(4). Rates of infection are highest among children, but rates of serious illness and death are highest among persons aged >65 years, children aged <2 years, and persons of any age who have medical conditions that place them at increased risk for complications from influenza (2,(5)(6)(7). Influenza vaccination is the primary method for preventing influenza and its severe complications. In this report from the Advisory Committee on Immunization Practices (ACIP), the primary target groups recommended for annual vaccination are 1) persons at increased risk for influenza-related complications (i.e., those aged >65 years, children aged 6-23 months, pregnant women, and persons of any age with certain chronic medical conditions); 2) persons aged 50-64 years because this group has an elevated prevalence of certain chronic medical conditions; and 3) persons who live with or care for persons at high risk (e.g., health-care workers and household contacts who have frequent contact with persons at high risk and who can transmit influenza to those persons at high risk). Vaccination is associated with reductions in influenza-related respiratory illness and physician visits among all age groups, hospitalization and death among persons at high risk, otitis media among children, and work absenteeism among adults (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Although influenza vaccination levels increased substantially during the 1990s, further improvements in vaccine coverage levels are needed, chiefly among persons aged 65 years, among children aged 6-23 months, and among health-care workers. ACIP recommends using strategies to improve vaccination levels, including using reminder/recall systems and standing orders programs (19)(20)(21). Although influenza vaccination remains the cornerstone for the control and treatment of influenza, information on antiviral medications is also presented because these agents are an adjunct to vaccine. # Primary Changes and Updates in the Recommendations The 2005 recommendations include five principal changes or updates: - ACIP recommends that persons with any condition (e.g., cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders) that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk for aspiration be vaccinated against influenza (see Target Groups for Vaccination). - ACIP emphasizes that all health-care workers should be vaccinated against influenza annually, and that facilities that employ health-care workers be strongly encouraged to provide vaccine to workers by using approaches that maximize immunization rates. - Use of both available vaccines (inactivated and LAIV) is encouraged for eligible persons every influenza season, especially persons in recommended target groups. During periods when inactivated vaccine is in short supply, use of LAIV is especially encouraged when feasible for eligible persons (including health-care workers) because use of LAIV by these persons might considerably increase availability of inactivated vaccine for persons in groups at high risk. - CDC and other agencies will assess the vaccine supply throughout the manufacturing period and will make recommendations preceding the 2005-06 influenza season regarding the need for tiered timing of vaccination of different risk groups. In addition, CDC will publish ACIP recommendations regarding inactivated vaccine subprioritization (tiering) on a later date in MMWR. # Influenza and Its Burden # Biology of Influenza Influenza A and B are the two types of influenza viruses that cause epidemic human disease (22). Influenza A viruses are further categorized into subtypes on the basis of two surface antigens: hemagglutinin and neuraminidase. Influenza B viruses are not categorized into subtypes. Since 1977, influenza A (H1N1) viruses, influenza A (H3N2) viruses, and influenza B viruses have been in global circulation. In 2001, influenza A (H1N2) viruses that probably emerged after genetic reassortment between human A (H3N2) and A (H1N1) viruses began circulating widely. Both influenza A and B viruses are further separated into groups on the basis of antigenic characteristics. New influenza virus variants result from frequent antigenic change (i.e., antigenic drift) resulting from point mutations that occur during viral replication. Influenza B viruses undergo antigenic drift less rapidly than influenza A viruses. Immunity to the surface antigens, particularly the hemagglutinin, reduces the likelihood of infection and severity of disease if infection occurs (23). Antibody against one influenza virus type or subtype confers limited or no protection against another type or subtype of influenza. Furthermore, antibody to one antigenic variant of influenza virus might not completely protect against a new antigenic variant of the same type or subtype (24). Frequent development of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the usual incorporation of one or more new strains in each year's influenza vaccine. # Clinical Signs and Symptoms of Influenza Influenza viruses are spread from person to person primarily through the coughing and sneezing of infected persons (22). The typical incubation period for influenza is 1-4 days, with an average of 2 days (25). Adults can be infectious from the day before symptoms begin through approximately 5 days after illness onset. Children can be infectious for >10 days, and young children can shed virus for several days before their illness onset. Severely immunocompromised persons can shed virus for weeks or months (26)(27)(28)(29). Uncomplicated influenza illness is characterized by the abrupt onset of constitutional and respiratory signs and symptoms (e.g., fever, myalgia, headache, malaise, nonproductive cough, sore throat, and rhinitis) (30). Among children, otitis media, nausea, and vomiting are also commonly reported with influenza illness (31)(32)(33). Respiratory illness caused by influenza is difficult to distinguish from illness caused by other respiratory pathogens on the basis of symptoms alone (see Role of Laboratory Diagnosis). Reported sensitivities and speci-ficities of clinical definitions for influenza-like illness (ILI) in studies primarily among adults that include fever and cough have ranged from 63% to 78% and 55% to 71%, respectively, compared with viral culture (34,35). Sensitivity and predictive value of clinical definitions can vary, depending on the degree of co-circulation of other respiratory pathogens and the level of influenza activity (36). A study among older nonhospitalized patients determined that symptoms of fever, cough, and acute onset had a positive predictive value of 30% for influenza (37), whereas a study of hospitalized older patients with chronic cardiopulmonary disease determined that a combination of fever, cough, and illness of <7 days was 78% sensitive and 73% specific for influenza (38). However, a study among vaccinated older persons with chronic lung disease reported that cough was not predictive of influenza infection, although having a fever or feverishness was 68% sensitive and 54% specific for influenza infection (39). Influenza illness typically resolves after 3-7 days for the majority of persons, although cough and malaise can persist for >2 weeks. Among certain persons, influenza can exacerbate underlying medical conditions (e.g., pulmonary or cardiac disease), lead to secondary bacterial pneumonia or primary influenza viral pneumonia, or occur as part of a coinfection with other viral or bacterial pathogens (40). Young children with influenza infection can have initial symptoms mimicking bacterial sepsis with high fevers (41,42), and <20% of children hospitalized with influenza can have febrile seizures (32,43). Influenza infection has also been associated with encephalopathy, transverse myelitis, Reye syndrome, myositis, myocarditis, and pericarditis (32,40,44,45). # Hospitalizations and Deaths from Influenza The risks for complications, hospitalizations, and deaths from influenza are higher among persons aged >65 years, young children, and persons of any age with certain underlying health conditions (see Persons at Increased Risk for Complications) than among healthy older children and younger adults (1,6,8,(46)(47)(48)(49)(50)(51)(52). Estimated rates of influenza-associated hospitalizations have varied substantially by age group in studies conducted during different influenza epidemics (Table 1). Among children aged 0-4 years, hospitalization rates have ranged from approximately 500/100,000 children for those with high-risk medical conditions to 100/100,000 children for those without high-risk medical conditions (53)(54)(55)(56). Within the 0-4 year age group, hospitalization rates are highest among children aged 0-1 years and are comparable to rates reported among persons aged >65 years (55,56) (Table 1). During influenza epidemics from 1979-80 through 2000-01, the estimated overall number of influenzaassociated hospitalizations in the United States ranged from approximately 54,000 to 430,000/epidemic. An average of approximately 226,000 influenza-related excess hospitalizations occurred per year, with 63% of all hospitalizations occurring among persons aged >65 years (57). Since the 1968 influenza A (H3N2) virus pandemic, the greatest numbers of influenza-associated hospitalizations have occurred during epidemics caused by type A (H3N2) viruses (58). Influenza-related deaths can result from pneumonia and from exacerbations of cardiopulmonary conditions and other chronic diseases. Deaths of older adults account for >90% of deaths attributed to pneumonia and influenza (1,52). In one study of influenza epidemics, approximately 19,000 influenzaassociated pulmonary and circulatory deaths per influenza season occurred during 1976-1990, compared with approximately 36,000 deaths during 1990-1999 (1). Estimated rates of influenza-associated pulmonary and circulatory deaths/ 100,000 persons were 0.4-0.6 among persons aged 0-49 years, 7.5 among persons aged 50-64 years, and 98.3 among persons aged >65 years. In the United States, the number of influenza-associated deaths might be increasing in part because the number of older persons is increasing (59). In addition, influenza seasons in which influenza A (H3N2) viruses predominate are associated with higher mortality (60); influenza A (H3N2) viruses predominated in 90% of influenza seasons during 1990-1999, compared with 57% of seasons during 1976-1990 (1). Deaths from influenza are uncommon among both children with and without high-risk conditions, but do occur (61,62). A study that modeled influenza-related deaths estimated that an average of 92 deaths (0.4 deaths per 100,000) occurred among children aged 65 years (1). Reports of 153 laboratoryconfirmed influenza-related pediatric deaths from 40 states during the 2003-04 influenza season indicated that 61 (40%) were aged <2 years and, of 92 children aged 2-17 years, 64 (70%) did not have an underlying medical condition traditionally considered to place a person at risk for influenzarelated complications (CDC, National Center for Infectious Diseases, unpublished data, 2005). Further information is needed regarding the risk for severe influenza-complications and optimal strategies for minimizing severe disease and death among children. # Options for Controlling Influenza In the United States, the primary option for reducing the effect of influenza is immunoprophylaxis with vaccine. Inactivated (i.e., killed virus) influenza vaccine and live, attenuated influenza vaccine are available for use in the United States (see Recommendations for Using Inactivated and Live, At- * Outcomes were limited to hospitalizations in which either pneumonia or influenza was listed as the first condition on discharge records (Simonsen) or included anywhere in the list of discharge diagnoses (Barker). † † † Source: Simonsen L, Fukuda K, Schonberger LB, Cox NJ. Impact of influenza epidemics on hospitalizations. J Infect Dis 2000;181:831-7. § § § Persons at high risk and not at high risk for influenza-related complications are combined. ¶ ¶ ¶ The low estimate is the average during influenza A (H1N1) or influenza B-predominate seasons, and the high estimate is the average during influenza A (H3N2)-predominate seasons. Outcomes were for rate of primary respiratory and circulatory hospitalizations. † † † † Source: Thompson # Influenza Vaccine Composition Both the inactivated and live, attenuated vaccines prepared for the 2005-06 season will include A/California/7/2004 (H3N2)-like, A/New Caledonia/20/99 (H1N1)-like, and B/Shanghai/361/2002-like antigens. For the A/California/7/ 2004 (H3N2)-like antigen, manufacturers may use the antigenically equivalent A/New York/55/2004 (H3N2) virus, and for the B/Shanghai/361/2002-like antigen, manufacturers may use the antigenically equivalent B/Jilin/20/2003 virus or B/Jiangsu/10/2003 virus. These viruses will be used because of their growth properties and because they are representative of influenza viruses likely to circulate in the United States during the 2005-06 influenza season. Because circulating influenza A (H1N2) viruses are a reassortant of influenza A (H1N1) and (H3N2) viruses, antibody directed against influenza A (H1N1) and influenza (H3N2) vaccine strains provides protection against circulating influenza A (H1N2) viruses. Influenza viruses for both the inactivated and live attenuated influenza vaccines are initially grown in embryonated hens eggs. Thus, both vaccines might contain limited amounts of residual egg protein. For the inactivated vaccine, the vaccine viruses are made noninfectious (i.e., inactivated or killed) (63). Subvirion and purified surface antigen preparations of the inactivated vaccine are available. Manufacturing processes differ by manufacturer. Manufacturers might use different compounds to inactivate influenza viruses and add antibiotics to prevent bacterial contamination. Package inserts should be consulted for additional information. # Thimerosal Thimerosal, a mercury-containing compound, has been used as a preservative in vaccines (64) since the 1930s and is used in multi-dose vials of inactivated influenza vaccine to reduce the likelihood of bacterial contamination. Although no scientific evidence indicates that thimerosal in vaccines leads to serious adverse events in vaccine recipients, in 1999, the U.S. Public Health Service and other organizations recommended that efforts be made to eliminate or reduce the thimerosal content in vaccines to decrease total mercury exposure, chiefly among infants (64)(65)(66). Since mid-2001, vaccines routinely recommended for infants in the United States have been manufactured either without or with only trace amounts of thimerosal to provide a substantial reduction in the total mercury exposure from vaccines for children (67). Vaccines containing trace amounts of thimerosal have <1 mcg mercury/dose. Influenza Vaccines and Thimerosal. LAIV does not contain thimerosal. Thimerosal preservative-containing inactivated influenza vaccines, distributed in multi-dose containers in the United States, contain 25 mcg of mercury/0.5-mL dose (64,65). Inactivated influenza virus vaccines distributed in the United States will also be available in 2005 in a thimerosal-free formulation in both 0.25 mL and 0.5-mL single-dose syringes and a preservative-free formulation (which contains trace amounts of thimerosal) in 0.25-mL-dose syringes. Influenza vaccine is part of the routine childhood immunization schedule. Sanofi Pasteur, Inc. (formerly Aventis Pas-teur, Inc.) produces FluZone ® , which is an inactivated influenza vaccine approved by the Food and Drug Administration (FDA) for persons aged >6 months. FluZone that is available in multi-dose vials contains thimerosal as a preservative. Thimerosal-free FluZone packaged as 0.25-mL unit dose syringes is available for use among persons aged 6-35 months. Thimerosal-free FluZone packaged as 0.5 mL unit dose syringes is available for use among persons aged >3 years. Fluvirin ® , produced by Chiron, is an inactivated influenza vaccine available in a preservative-free formulation, is packaged as 0.5-mL single-dose syringes, and is licensed for use in persons aged >4 years. The preservative-free Fluvirin vaccine contains trace amounts of thimerosal. The total amount of inactivated influenza vaccine available without thimerosal as a preservative will be increased as manufacturing capabilities are expanded. The risks for severe illness from influenza infection are elevated among both young children and pregnant women, and both groups benefit from vaccination by preventing illness and death from influenza. In contrast, no scientifically conclusive evidence exists of harm from exposure to thimerosal preservative-containing vaccine, whereas evidence is accumulating of lack of any harm resulting from exposure to such vaccines (64,68). Therefore, the benefits of influenza vaccination outweigh the theoretical risk, if any, for thimerosal exposure through vaccination. Nonetheless, certain persons remain concerned regarding exposure to thimerosal. The U.S. vaccine supply for infants and pregnant women is in a period of transition during which the availability of thimerosal-reduced or thimerosal-free vaccine intended for these groups is being expanded by manufacturers as a feasible means of reducing an infant's total exposure to mercury because other environmental sources of exposure are more difficult or impossible to eliminate. Reductions in thimerosal in other vaccines have been achieved already and have resulted in substantially lowered cumulative exposure to thimerosal from vaccination among infants and children. For all of these reasons, persons recommended to receive inactivated influenza vaccine may receive either vaccine preparation, depending on availability. # Efficacy and Effectiveness of Inactivated Influenza Vaccine The effectiveness of inactivated influenza vaccine depends primarily on the age and immunocompetence of the vaccine recipient and the degree of similarity between the viruses in the vaccine and those in circulation. The majority of vaccinated children and young adults develop high postvaccination hemagglutination inhibition antibody titers (69)(70)(71). These antibody titers are protective against illness caused by strains that are antigenically similar to those strains of the same type or subtype included in the vaccine (70)(71)(72)(73). Adults Aged <65 Years. When the vaccine and circulating viruses are antigenically similar, influenza vaccine prevents influenza illness among approximately 70%-90% of healthy adults aged <65 years (9,12,74,75). Vaccination of healthy adults also has resulted in decreased work absenteeism and decreased use of health-care resources, including use of antibiotics, when the vaccine and circulating viruses are wellmatched (9)(10)(11)(12)75,76). In a case-control study of adults aged 50-64 years with laboratory-confirmed influenza during the 2003-04 season when the vaccine and circulating viruses were not well matched, vaccine effectiveness was estimated to be 52% among healthy persons and 38% among those with one or more high-risk conditions (77). Children. Children aged 6 months can develop protective levels of anti-influenza antibody against specific influenza virus strains after influenza vaccination (69,70,(78)(79)(80)(81), although the antibody response among children at high risk for influenza-related complications might be lower than among healthy children (82,83). In a randomized study among children aged 1-15 years, inactivated influenza vaccine was 77%-91% effective against influenza respiratory illness and was 44%-49%, 74%-76%, and 70%-81% effective against influenza seroconversion among children aged 1-5, 6-10, and 11-15 years, respectively (71). One study (84) reported a vaccine efficacy of 56% against influenza illness among healthy children aged 3-9 years, and another study (85) determined vaccine efficacy of 22%-54% and 60%-78% among children with asthma aged 2-6 years and 7-14 years, respectively. A 2-year randomized study of children aged 6-24 months determined that >89% of children seroconverted to all three vaccine strains during both years (86). During year 1, among 411 children, vaccine efficacy was 66% (95% confidence interval = 34%-82%) against culture-confirmed influenza (attack rates: 5.5% and 15.9% among vaccine and placebo groups, respectively). During year 2, among 375 children, vaccine efficacy was -7% (95% CI = -247%-67%; attack rates: 3.6% and 3.3% among vaccine and placebo groups, respectively; the second year exhibited lower attack rates overall and was considered a mild season). However, no overall reduction in otitis media was reported. Other studies report that trivalent inactivated influenza vaccine decreases the incidence of influenza-associated otitis media among young children by approximately 30% (16,17). A retrospective study among approximately 5,000 children aged 6-23 months conducted during a year with a suboptimal vaccine match indicated vaccine effectiveness of 49% against medically attended, clinically diagnosed pneumonia or influenza (International Classification of Diseases, Ninth Revision codes 480-487) among children who had received 2 doses of influenza vaccine. No effectiveness was demonstrated among children who had received only 1 dose of influenza vaccine, illustrating the importance of administering 2 doses of vaccine to previously unvaccinated children aged <9 years (87). Adults Aged >65 Years. Older persons and persons with certain chronic diseases might develop lower postvaccination antibody titers than healthy young adults and thus can remain susceptible to influenza infection and influenza-related upper respiratory tract illness (88)(89)(90). A randomized trial among noninstitutionalized persons aged >60 years reported a vaccine efficacy of 58% against influenza respiratory illness, but indicated that efficacy might be lower among those aged >70 years (91). The vaccine can also be effective in preventing secondary complications and reducing the risk for influenzarelated hospitalization and death among adults aged >65 years with and without high-risk medical conditions (e.g., heart disease and diabetes) (13)(14)(15)18,92). Among elderly persons not living in nursing homes or similar chronic-care facilities, influenza vaccine is 30%-70% effective in preventing hospitalization for pneumonia and influenza (15,93). Among older persons who do reside in nursing homes, influenza vaccine is most effective in preventing severe illness, secondary complications, and deaths. Among this population, the vaccine can be 50%-60% effective in preventing influenza-related hospitalization or pneumonia and 80% effective in preventing influenza-related death, although the effectiveness in preventing influenza illness often ranges from 30% to 40% (94)(95)(96). # Efficacy and Effectiveness of LAIV Healthy Children. A randomized, double-blind, placebocontrolled trial among 1,602 healthy children initially aged 15-71 months assessed the efficacy of trivalent LAIV against culture-confirmed influenza during two seasons (97,98). This trial included subsets of 238 Children who continued in the study remained in the same study group. In season one, when vaccine and circulating virus strains were well-matched, efficacy was 93% for all participants, regardless of age, among persons receiving 2 doses of LAIV. Efficacy was 87% in the 60-71-month subset for those who received 2 doses, and was 91% in the subset for those who received 1 or 2 doses. In season two, when the A (H3N2) component was not well-matched between vaccine and circulating virus strains, efficacy was 86% overall and 87% among those aged 60-84 months. The vaccine was 92% effi-cacious in preventing culture-confirmed influenza during the two-season study. Other results included a 27% reduction in febrile otitis media and a 28% reduction in otitis media with concomitant antibiotic use. Receipt of LAIV also resulted in a 30% lower incidence of febrile otitis media and 21% fewer febrile illnesses. Another study assessing LAIV effectiveness in children aged 18 months-18 years indicated effectiveness against medically attended acute respiratory illness (MAARI) of 18%. However, applying a validation sample of surveillance cultures with MAARI demonstrated efficacy of 92% against influenza A (H1N1) and 66% against an influenza B drift variant (99). Healthy Adults. A randomized, double-blind, placebocontrolled trial among 4,561 healthy working adults aged 18-64 years assessed multiple endpoints, including reductions in illness, absenteeism, health-care visits, and medication use during peak and total influenza outbreak periods (100). The study was conducted during the 1997-98 influenza season, when the vaccine and circulating A (H3N2) strains were not wellmatched. The study did not include testing of viruses by a laboratory. During peak outbreak periods, no difference was identified between LAIV and placebo recipients experiencing any febrile episodes. However, vaccination was associated with reductions in severe febrile illnesses of 19% and febrile upper respiratory tract illnesses of 24%. Vaccination also was associated with fewer days of illness, fewer days of work lost, fewer days with health-care-provider visits, and reduced use of prescription antibiotics and over-the-counter medications. Among the subset of 3,637 healthy adults aged 18-49 years, LAIV recipients (n = 2,411) had 26% fewer febrile upperrespiratory illness episodes; 27% fewer lost work days as a result of febrile upper respiratory illness; and 18%-37% fewer days of health-care provider visits caused by febrile illness, compared with placebo recipients (n = 1,226). Days of antibiotic use were reduced by 41%-45% in this age subset. Another randomized, double-blind, placebo-controlled challenge study among 92 healthy adults (LAIV, n = 29; placebo, n = 31; inactivated influenza vaccine, n = 32) aged 18-41 years assessed the efficacy of both LAIV and inactivated vaccine (101). The overall efficacy of LAIV and inactivated influenza vaccine in preventing laboratory-documented influenza from all three influenza strains combined was 85% and 71%, respectively, on the basis of experimental challenge by viruses to which study participants were susceptible before vaccination. The difference in efficacy between the two vaccines was not statistically significant. # Cost-Effectiveness of Influenza Vaccine Influenza vaccination can reduce both health-care costs and productivity losses associated with influenza illness. Economic studies of influenza vaccination of persons aged >65 years conducted in the United States have reported overall societal cost savings and substantial reductions in hospitalization and death (15,93,102). Studies of adults aged 65 years, vaccination resulted in a net savings per quality-adjusted life year (QALY) gained and resulted in costs of $23-$256/QALY among younger age groups. Additional studies of the relative cost-effectiveness and cost utility of influenza vaccination among children and among adults aged <65 years are needed and should be designed to account for year-to-year variations in influenza attack rates, illness severity, and vaccine efficacy when evaluating the longterm costs and benefits of annual vaccination. # Vaccination Coverage Levels One of the national health objectives for 2010 is to achieve vaccination coverage for 90% of persons aged >65 years (objective no. 14-29a) (111). Among persons aged >65 years, influenza vaccination levels increased from 33% in 1989 (112) to 66% in 1999 (113), surpassing the Healthy People 2000 objective of 60% (114). Vaccine coverage in this group reached the highest levels recorded (68%) during the 1999-00 influenza season, using the percentage of adults reporting influenza vaccination during the previous 12 months who participated in the National Health Interview Survey (NHIS) during the first and second quarters of each calendar year as a proxy measure of influenza vaccine coverage for the previous § Persons categorized as being at high risk for influenza-related complications self-reported one or more of the following: 1) ever being told by a physician they had diabetes, emphysema, coronary heart disease, angina, heart attack, or other heart condition; 2) having a diagnosis of cancer during the previous 12 months (excluding nonmelanoma skin cancer) or ever being told by a physician they have lymphoma, leukemia, or blood cancer during the previous 12 months; 3) being told by a physician they have chronic bronchitis or weak or failing kidneys; or 4) reporting an asthma episode or attack during the preceding 12 months. ¶ Aged 18-44 years, pregnant at the time of the survey and without high-risk conditions. Adults were classified as health-care workers if they were currently employed in a health-care occupation or in a health-care-industry setting, on the basis of standard occupation and industry categories recoded in groups by CDC's National Center for Health Statistics. † † Interviewed adult in each household containing at least one of the following: a child aged 65 years, or any person aged 2-17 years at high risk (see previous footnote § ). To obtain information on household composition and high-risk status of household members, the sampled adult, child, and person files from NHIS were merged. Interviewed adults who were health-care workers or who had high-risk conditions were excluded. Information could not be assessed regarding high-risk status of other adults aged 18-64 years in the household, thus, certain adults 18-64 years who live with an adult aged 18-64 years at high risk were not included in the analysis. influenza season (113). Possible reasons for the increase in influenza vaccination levels among persons aged >65 years through the 1999-00 influenza season include 1) greater acceptance of preventive medical services by practitioners; 2) increased delivery and administration of vaccine by healthcare providers and sources other than physicians; 3) new information regarding influenza vaccine effectiveness, cost-effectiveness, and safety; and 4) initiation of Medicare reimbursement for influenza vaccination in 1993 (8,14,15,94,95,115,116). Vaccine coverage increased more rapidly through the mid-1990s than during subsequent seasons (average annual percentage increase of 4% from 1988-89 to 1996-97 versus 1% from 1996-97 to 1999-00) and has remained relatively stable since 2000. Estimated national influenza vaccine coverage in 2003 among persons aged >65 years and 50-64 years was 66% and 37%, respectively, based on 2003 NHIS data (Table 2). The estimated vaccination coverage among adults with high-risk conditions aged 18-49 years and 50-64 years was 24% and 46%, respectively, substantially lower than the Healthy People 2000 and 2010 objective of 60% (111,114). Continued annual monitoring is needed to determine the effects of vaccine supply delays and shortages, changes in influenza vaccination recommendations and target groups for vaccination, reimbursement rates for vaccine and vaccine administration, and other factors related to vaccination coverage among adults and children. New strategies to improve coverage will be needed to achieve the Healthy People 2010 objective (21). Reducing racial and ethnic health disparities, including disparities in vaccination coverage, is an overarching national goal (111). Although estimated influenza vaccination coverage for the 1999-00 season reached the highest levels recorded among older black, Hispanic, and white populations, vaccination levels among blacks and Hispanics continue to lag behind those among whites (113,117). Estimated vaccination coverage levels based on 2003 NHIS data among persons aged >65 years were 69% among non-Hispanic whites, 48% among non-Hispanic blacks, and 45% among Hispanics (CDC, National Immunization Program, unpublished data, 2005). Additional strate-gies are needed to achieve the Healthy People 2010 objectives among all racial and ethnic groups. In 1997 and 1998, vaccination coverage estimates among nursing home residents were 64%-82% and 83%, respectively (118,119). The Healthy People 2010 goal is to achieve influenza vaccination of 90% among nursing home residents, an increase from the Healthy People 2000 goal of 80% (111,114). Reported vaccination levels are low among children at increased risk for influenza complications. One study conducted among patients in health maintenance organizations reported influenza vaccination percentages ranging from 9% to 10% among children with asthma (120). A 25% vaccination level was reported among children with severe to moderate asthma who attended an allergy and immunology clinic (121). However, a study conducted in a pediatric clinic demonstrated an increase in the vaccination percentage of children with asthma or reactive airways disease from 5% to 32% after implementing a reminder/recall system (122). One study reported 79% vaccination coverage among children attending a cystic fibrosis treatment center (123) Vaccination of health-care workers has been associated with reduced work absenteeism (9) and fewer deaths among nursing home patients (125,126) and is a high priority for reducing the impact of influenza in health-care settings and for expanding influenza vaccine use (127,128). Limited information is available regarding use of influenza vaccine among pregnant women. Among women aged 18-44 years without diabetes responding to the 2001 BRFSS, those who were pregnant were less likely to report influenza vaccination during the previous 12 months (13.7%) than those not pregnant (16.8%) (122,129). Only 13% of pregnant women reported vaccination according to 2003 NHIS data, excluding pregnant women who reported diabetes, heart disease, lung disease, and other selected high-risk conditions (CDC, National Immunization Program, unpublished data, 2004) (Table 2). These data indicate low compliance with the ACIP recommendations for pregnant women. In a study of influenza vaccine acceptance by pregnant women, 71% who were offered the vaccine chose to be vaccinated (130). However, a 1999 survey of obstetricians and gynecologists determined that only 39% administered influenza vaccine to obstetric patients, although 86% agreed that pregnant women's risk for influenza-related morbidity and mortality increases during the last two trimesters (131). Recent data indicate that self-report of influenza vaccination among adults, compared with extraction from the medical record, is both sensitive and specific (132). Patient self-reports should be accepted as evidence of influenza vaccination in clinical practice (132). However, information on the validity of parents' reports of pediatric influenza vaccination is not yet available. # Recommendations for Using Inactivated and Live, Attenuated Influenza Vaccines Both the inactivated influenza vaccine and LAIV can be used to reduce the risk for influenza. LAIV is approved for use among healthy persons aged 5-49 years. Inactivated influenza vaccine is approved for persons aged >6 months, including those with high-risk conditions (see following sections on inactivated influenza vaccine and live, attenuated influenza vaccine). # Target Groups for Vaccination # Persons at Increased Risk for Complications Vaccination with inactivated influenza vaccine is recommended for the following persons who are at increased risk for complications from influenza: # Persons Aged 50-64 Years Vaccination is recommended for persons aged 50-64 years because this group has an increased prevalence of persons with high-risk conditions. In 2002, approximately 43.6 million persons in the United States were aged 50-64 years, of whom 13.5 million (34%) had one or more high-risk medical conditions (133). Influenza vaccine has been recommended for this entire age group to increase the low vaccination rates among persons in this age group with high-risk conditions (see preceding section). Age-based strategies are more successful in increasing vaccine coverage than patient-selection strategies based on medical conditions. Persons aged 50-64 years without high-risk conditions also receive benefit from vaccination in the form of decreased rates of influenza illness, decreased work absenteeism, and decreased need for medical visits and medication, including antibiotics (9-12). Furthermore, 50 years is an age when other preventive services begin and when routine assessment of vaccination and other preventive services has been recommended (134,135). # Persons Who Can Transmit Influenza to Those at High Risk Persons who are clinically or subclinically infected can transmit influenza virus to persons at high risk for complications from influenza. Decreasing transmission of influenza from caregivers and household contacts to persons at high risk might reduce influenza-related deaths among persons at high risk. Evidence from two studies indicates that vaccination of healthcare workers is associated with decreased deaths among nursing home patients (125,126), and hospital-based influenza outbreaks frequently occur where unvaccinated health-care workers are employed. Administration of LAIV has been dem-onstrated to reduce MAARI in contacts of vaccine recipients (136), and to reduce ILI-related economic and medical consequences (such as work days lost and number of health-care provider visits). In addition to health-care workers, additional groups that can transmit influenza to high-risk persons and that should be vaccinated include - employees of assisted living and other residences for persons in groups at high risk; - persons who provide home care to persons in groups at high risk; and - household contacts (including children) of persons in groups at high risk. In addition, because children aged 0-23 months are at increased risk for influenza-related hospitalization (54)(55)(56), vaccination is recommended for their household contacts and out-of-home caregivers, particularly for contacts of children aged 0-5 months, because influenza vaccines have not been approved by FDA for use among children aged <6 months (see Healthy Young Children). Healthy persons aged 5-49 years in these groups who are not contacts of severely immunosuppressed persons (see Live, Attenuated Influenza Vaccine Recommendations) can receive either LAIV or inactivated influenza vaccine. All other persons in this group should receive inactivated influenza vaccine. # Health-Care Workers All health-care workers should be vaccinated against influenza annually (128). Facilities that employ health-care workers are strongly encouraged to provide vaccine to workers by using approaches that maximize vaccination rates. This will protect health-care workers, their patients, and communities, and will improve prevention of influenza-associated disease, patient safety, and will reduce disease burden. Influenza vaccination rates among health-care workers should be regularly measured and reported. Although vaccination rates for healthcare workers are typically <40%, with moderate effort, organized campaigns can attain higher rates of vaccination among this population (127,137). Currently, seven states have legislation requiring annual influenza vaccination of health-care workers or the signing of an informed declination (128), and 15 states have regulations regarding vaccination of health-care workers in long-term-care facilities (138). Physicians, nurses, and other workers in both hospital and outpatient-care settings, including medical emergency-response workers (e.g., paramedics and emergency medical technicians), should be vaccinated, as should employees of nursing home and chroniccare facilities who have contact with patients or residents. # Additional Information Regarding Vaccination of Specific Populations Pregnant Women Influenza-associated excess deaths among pregnant women were documented during the pandemics of 1918-19 and 1957-58 (49,(139)(140)(141). Case reports and limited studies also indicate that pregnancy can increase the risk for serious medical complications of influenza (142)(143)(144)(145)(146). An increased risk might result from 1) increases in heart rate, stroke volume, and oxygen consumption; 2) decreases in lung capacity; and 3) changes in immunologic function during pregnancy. A study of the effect of influenza during 17 interpandemic influenza seasons demonstrated that the relative risk for hospitalization for selected cardiorespiratory conditions among pregnant women enrolled in Medicaid increased from 1.4 during weeks 14-20 of gestation to 4.7 during weeks 37-42, in comparison with women who were 1-6 months postpartum (147). Women in their third trimester of pregnancy were hospitalized at a rate (i.e., 250/100,000 pregnant women) comparable with that of nonpregnant women who had high-risk medical conditions. Researchers estimate that an average of 1-2 hospitalizations can be prevented for every 1,000 pregnant women vaccinated (147). Because of the increased risk for influenza-related complications, women who will be pregnant during the influenza season should be vaccinated. Vaccination can occur in any trimester. One study of influenza vaccination of approximately 2,000 pregnant women demonstrated no adverse fetal effects associated with influenza vaccine (148). # Healthy Young Children Studies indicate that rates of hospitalization are higher among young children than older children when influenza viruses are in circulation (53,55,56,149,150). The increased rates of hospitalization are comparable with rates for other groups considered at high risk for influenza-related complications. However, the interpretation of these findings has been confounded by co-circulation of respiratory syncytial viruses, which are a cause of serious respiratory viral illness among children and which frequently circulate during the same time as influenza viruses (151)(152)(153). One study assessed rates of influenza-associated hospitalizations among the entire U.S. population during 1979-2001 and calculated an average rate of approximately 108 hospitalizations per 100,000 personyears in children aged <5 years (46). Two recent studies have attempted to separate the effects of respiratory syncytial viruses and influenza viruses on rates of hospitalization among children who do not have high-risk conditions (54,55). Both studies reported that otherwise healthy children aged <2 years, and possibly children aged 2-4 years, are at increased risk for influenza-related hospitalization compared with older healthy children (Table 1). Among the Tennessee Medicaid population during 1973-1993, healthy children aged 6 months-<3 years had rates of influenza-associated hospitalization comparable with or higher than rates among children aged 3-14 years with high-risk conditions (54,56). Another Tennessee study reported a hospitalization rate per year of 3-4/1,000 healthy children aged <2 years for laboratory-confirmed influenza (33). Because children aged 6-23 months are at substantially increased risk for influenza-related hospitalizations, ACIP recommends vaccination of all children in this age group (154). ACIP continues to recommend influenza vaccination of persons aged >6 months who have high-risk medical conditions. The current inactivated influenza vaccine is not approved by FDA for use among children aged <6 months, the pediatric group at greatest risk for influenza-related complications (54). Vaccinating their household contacts and out-of-home caregivers might decrease the probability of influenza infection among these children. Beginning # Persons Infected with HIV Limited information is available regarding the frequency and severity of influenza illness or the benefits of influenza vaccination among persons with HIV infection (156,157). However, a retrospective study of young and middle-aged women enrolled in Tennessee's Medicaid program determined that the attributable risk for cardiopulmonary hospitalizations among women with HIV infection was higher during influenza seasons than during the peri-influenza periods. The risk for hospitalization was higher for HIV-infected women than for women with other well-recognized high-risk conditions, including chronic heart and lung diseases (158). Another study estimated that the risk for influenza-related death was 9.4-14.6/10,000 persons with acquired immunodeficiency syndrome (AIDS) compared with 0.09-0.10/10,000 among all persons aged 25-54 years and 6.4-7.0/10,000 among persons aged >65 years (159). Other reports indicate that influenza symptoms might be prolonged and the risk for complications from influenza increased for certain HIVinfected persons (160)(161)(162). Inactivated influenza vaccination has been demonstrated to produce substantial antibody titers against influenza among vaccinated HIV-infected persons who have minimal AIDSrelated symptoms and high CD4+ T-lymphocyte cell counts (163)(164)(165)(166). A limited, randomized, placebo-controlled trial determined that inactivated influenza vaccine was highly effective in preventing symptomatic, laboratory-confirmed influenza infection among HIV-infected persons with a mean of 400 CD4+ T-lymphocyte cells/mm3; a limited number of persons with CD4+ T-lymphocyte cell counts of 100 CD4+ cells and among those with <30,000 viral copies of HIV type-1/mL (162). Among persons who have advanced HIV disease and low CD4+ T-lymphocyte cell counts, inactivated influenza vaccine might not induce protective antibody titers (165,166); a second dose of vaccine does not improve the immune response in these persons (166,167). One study determined that HIV RNA (ribonucleic acid) levels increased transiently in one HIV-infected person after influenza infection (168). Studies have demonstrated a transient (i.e., 2-4 week) increase in replication of HIV-1 in the plasma or peripheral blood mononuclear cells of HIV-infected persons after vaccine administration (165,169). Other studies using similar laboratory techniques have not documented a substantial increase in the replication of HIV (170)(171)(172)(173). Deterioration of CD4+ T-lymphocyte cell counts or progression of HIV disease have not been demonstrated among HIVinfected persons after influenza vaccination compared with unvaccinated persons (166,174). Limited information is available concerning the effect of antiretroviral therapy on increases in HIV RNA levels after either natural influenza infection or influenza vaccination (156,175). Because influenza can result in serious illness and because vaccination with inactivated influenza vaccine can result in the production of protective antibody titers, vaccination will benefit HIV-infected persons, including HIV-infected pregnant women. # Breastfeeding Mothers Influenza vaccine is safe for mothers who are breastfeeding and their infants. Breastfeeding does not adversely affect the immune response and is not a contraindication for vaccination. # Travelers The risk for exposure to influenza during travel depends on the time of year and destination. In the tropics, influenza can occur throughout the year. In the temperate regions of the Southern Hemisphere, the majority of influenza activity occurs during April-September. In temperate climate zones of the Northern and Southern Hemispheres, travelers also can be exposed to influenza during the summer, especially when traveling as part of large organized tourist groups (e.g., on cruise ships) that include persons from areas of the world where influenza viruses are circulating (176,177). Persons at high risk for complications of influenza who were not vaccinated with influenza vaccine during the preceding fall or winter should consider receiving influenza vaccine before travel if they plan to - travel to the tropics, - travel with organized tourist groups at any time of year, or - travel to the Southern Hemisphere during April-September. No information is available regarding the benefits of revaccinating persons before summer travel who were already vaccinated in the preceding fall. Persons at high risk who receive the previous season's vaccine before travel should be revaccinated with the current vaccine the following fall or winter. Persons aged >50 years and persons at high risk should consult with their physicians before embarking on travel during the summer to discuss the symptoms and risks for influenza and the advisability of carrying antiviral medications for either prophylaxis or treatment of influenza. # General Population In addition to the groups for which annual influenza vaccination is recommended, physicians should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza or transmitting influenza to others should they become infected (the vaccine can be administered to children aged >6 months), depending on vaccine availability (see Influenza Vaccine Supply). Persons who provide essential community services should be considered for vaccination to minimize disruption of essential activities during influenza outbreaks. Students or other persons in institutional settings (e.g., those who reside in dormitories) should be encouraged to receive vaccine to minimize the disruption of routine activities during epidemics. # Comparison of LAIV with Inactivated Influenza Vaccine Both inactivated influenza vaccine and LAIV are available to reduce the risk for influenza infection and illness. However, the vaccines also differ in key ways (Table 3). # Major Similarities LAIV and inactivated influenza vaccine contain strains of influenza viruses that are antigenically equivalent to the annually recommended strains: one influenza A (H3N2) virus, one A (H1N1) virus, and one B virus. Each year, one or more virus strains might be changed on the basis of global surveillance for influenza viruses and the emergence and spread of new strains. Viruses for both vaccines are grown in eggs. Both vaccines are administered annually to provide optimal protection against influenza infection (Table 3). # Major Differences Inactivated influenza vaccine contains killed viruses, whereas LAIV contains live, attenuated viruses still capable of replication. LAIV is administered intranasally by sprayer, whereas inactivated influenza vaccine is administered intramuscularly by injection. LAIV is more expensive than inactivated influenza vaccine, although the price differential between inactivated vaccine and LAIV has decreased for the 2005-06 season. LAIV is approved for use among healthy persons aged 5-49 years; inactivated influenza vaccine is approved for use among persons aged >6 months, including those who are healthy and those with chronic medical conditions (Table 3). # Inactivated Influenza Vaccine Recommendations Persons Who Should Not Be Vaccinated with Inactivated Influenza Vaccine Inactivated influenza vaccine should not be administered to persons known to have anaphylactic hypersensitivity to eggs or to other components of the influenza vaccine without first consulting a physician (see Side Effects and Adverse Reactions). Prophylactic use of antiviral agents is an option for preventing influenza among such persons. However, persons who have a history of anaphylactic hypersensitivity to vaccine components but who are also at high risk for complications from influenza can benefit from vaccine after appropriate allergy evaluation and desensitization. Information regarding vaccine components is located in package inserts from each manufacturer. Persons with acute febrile illness usually should not be vaccinated until their symptoms have abated. However, minor illnesses with or without fever do not contraindicate use of influenza vaccine, particularly among children with mild upper-respiratory-tract infection or allergic rhinitis. Immunogenicity and side effects of split-and whole-virus vaccines are similar among adults when vaccines are administered at the recommended dosage. § For adults and older children, the recommended site of vaccination is the deltoid muscle. The preferred site for infants and young children is the anterolateral aspect of the thigh. ¶ Two doses administered at least 1 month apart are recommended for children aged <9 years who are receiving influenza vaccine for the first time. # Dosage Dosage recommendations vary according to age group (Table 4). Among previously unvaccinated children aged 1 month apart are recommended for satisfactory antibody responses. If possible, the second dose should be administered before December. If a child aged <9 years receiving vaccine for the first time does not receive a second dose of vaccine within the same season, only 1 dose of vaccine should be administered the following season. Two doses are not required at that time. Among adults, studies have indicated limited or no improvement in antibody response when a second dose is administered during the same season (178)(179)(180). Even when the current influenza vaccine contains one or more antigens administered in previous years, annual vaccination with the current vaccine is necessary because immunity declines during the year after vaccination (181,182). Vaccine prepared for a previous influenza season should not be administered to provide protection for the current season. Because of lack of vaccine efficacy data, ACIP does not recommend that a child receiving influenza vaccine for the first time be given the first dose of vaccine in the spring, followed by the second dose in the autumn of the same year. # Route The intramuscular route is recommended for influenza vaccine. Adults and older children should be vaccinated in the deltoid muscle. A needle length >1 inch can be considered for these age groups because needles <1 inch might be of insufficient length to penetrate muscle tissue in certain adults and older children (183). Infants and young children should be vaccinated in the anterolateral aspect of the thigh (67). ACIP recommends a needle length of 7/8-1 inch for children aged <12 months for intramuscular vaccination into the anterolateral thigh. When injecting into the deltoid muscle among children with adequate deltoid muscle mass, a needle length of 7/8-1.25 inches is recommended (67). # Side Effects and Adverse Reactions When educating patients regarding potential side effects, clinicians should emphasize that 1) inactivated influenza vaccine contains noninfectious killed viruses and cannot cause influenza; and 2) coincidental respiratory disease unrelated to influenza vaccination can occur after vaccination. # Local Reactions In placebo-controlled studies among adults, the most frequent side effect of vaccination is soreness at the vaccination site (affecting 10%-64% of patients) that lasts <2 days (12,(184)(185)(186). These local reactions typically are mild and rarely interfere with the person's ability to conduct usual daily activities. One blinded, randomized, cross-over study among 1,952 adults and children with asthma, demonstrated that only body aches were reported more frequently after inactivated influenza vaccine (25.1%) than placebo-injection (20.8%) (187). One study (83) reported 20%-28% of children with asthma aged 9 months-18 years with local pain and swelling, and another study (80) reported 23% of children aged 6 months-4 years with chronic heart or lung disease had local reactions. A different study (81) reported no difference in local reactions among 53 children aged 6 months-6 years with high-risk medical conditions or among 305 healthy children aged 3-12 years in a placebo-controlled trial of inactivated influenza vaccine. In a study of 12 children aged 5-32 months, no substantial local or systemic reactions were noted (188). # Systemic Reactions Fever, malaise, myalgia, and other systemic symptoms can occur after vaccination with inactivated vaccine and most often affect persons who have had no previous exposure to the influenza virus antigens in the vaccine (e.g., young children) (189,190). These reactions begin 6-12 hours after vaccination and can persist for 1-2 days. Recent placebo-controlled trials demonstrate that among older persons and healthy young adults, administration of split-virus influenza vaccine is not associated with higher rates of systemic symptoms (e.g., fever, malaise, myalgia, and headache) when compared with placebo injections (12,(184)(185)(186). Less information from published studies is available for children, compared with adults. However, in a randomized crossover study among both children and adults with asthma, no increase in asthma exacerbations was reported for either age group (187). An analysis of 215,600 children aged <18 years and 8,476 children aged 6-23 months enrolled in one of five health maintenance organizations reported no increase in biologically plausible medically attended events during the 2 weeks after inactivated influenza vaccination, compared with control periods 3-4 weeks before and after vaccination (191). In a study of 791 healthy children (71), postvaccination fever was noted among 11.5% of children aged 1-5 years, 4.6% among children aged 6-10 years, and 5.1% among children aged 11-15 years. Among children with high-risk medical conditions, one study of 52 children aged 6 months-4 years reported fever among 27% and irritability and insomnia among 25% (80); and a study among 33 children aged 6-18 months reported that one child had irritability and one had a fever and seizure after vaccination (192). No placebo comparison was made in these studies. However, in pediatric trials of A/New Jersey/76 swine influenza vaccine, no difference was reported between placebo and split-virus vaccine groups in febrile reactions after injection, although the vaccine was associated with mild local tenderness or erythema (81). Limited data regarding potential adverse events after influenza vaccination are available from the Vaccine Adverse Event Reporting System (VAERS). During January 1, 1991-June 30, 2004, VAERS received 1,895 reports of adverse events among children aged <18 years, including 479 reports of adverse events among children aged 6-23 months. The number of influenza vaccine doses received by children during this entire period is unknown (CDC, unpublished data, 2005). A recently published review of VAERS reports of trivalent inactivated influenza vaccine (TIV) in children aged 6-23 months documented that the most frequently reported adverse events were fever, rash, injection-site reactions, and seizures. The majority of the small total number of reported seizures appeared to be febrile (193). Because of the limitations of passive reporting systems, determining causality for specific types of adverse events, with the exception of injection-site reactions, is usually not possible by using VAERS data alone. A population-based study of TIV safety in children aged 6-23 months indicated no vaccine associated adverse events that had a plausible relationship to vaccination (194). Health-care professionals should promptly report to VAERS all clinically significant adverse events after influenza vaccination of children, even if the health-care professional is not certain that the vaccine caused the event. The Institute of Medicine has specifically recommended reporting of potential neurologic complications (e.g., demyelinating disorders such as Guillain-Barré syndrome ), although no evidence exists of a causal relationship between influenza vaccine and neurologic disorders in children. Immediate -presumably allergic -reactions (e.g., hives, angioedema, allergic asthma, and systemic anaphylaxis) rarely occur after influenza vaccination (195). These reactions probably result from hypersensitivity to certain vaccine components; the majority of reactions probably are caused by residual egg protein. Although current influenza vaccines contain only a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Persons who have had hives or swelling of the lips or tongue, or who have experienced acute respiratory distress or collapse after eating eggs should consult a physician for appropriate evaluation to help determine if vaccine should be administered. Persons who have documented immunoglobulin E (IgE)-mediated hypersensitivity to eggs, including those who have had occupational asthma or other allergic responses to egg protein, might also be at increased risk for allergic reactions to influenza vaccine, and consultation with a physician should be considered. Protocols have been published for safely administering influenza vaccine to persons with egg allergies (196)(197)(198). Hypersensitivity reactions to any vaccine component can occur. Although exposure to vaccines containing thimerosal can lead to induction of hypersensitivity, the majority of patients do not have reactions to thimerosal when it is administered as a component of vaccines, even when patch or intradermal tests for thimerosal indicate hypersensitivity (199,200). When reported, hypersensitivity to thimerosal usually has consisted of local, delayed hypersensitivity reactions (199). # Guillain-Barré Syndrome The 1976 swine influenza vaccine was associated with an increased frequency of GBS (201,202). Among persons who received the swine influenza vaccine in 1976, the rate of GBS was 25 years than persons <25 years (201). Evidence for a causal relation of GBS with subsequent vaccines prepared from other influenza viruses is unclear. Obtaining strong epidemiologic evidence for a possible limited increase in risk is difficult for such a rare condition as GBS, which has an annual incidence of 10-20 cases/1 million adults (203). More definitive data probably will require using other methodologies (e.g., laboratory studies of the pathophysiology of GBS). During three of four influenza seasons studied during 1977-1991, the overall relative risk estimates for GBS after influenza vaccination were slightly elevated but were not statistically significant in any of these studies (204)(205)(206). However, in a study of the 1992-93 and 1993-94 seasons, the overall relative risk for GBS was 1.7 (95% CI = 1.0-2.8; p = 0.04) during the 6 weeks after vaccination, representing approximately 1 additional case of GBS/1 million persons vaccinated. The combined number of GBS cases peaked 2 weeks after vaccination (207). Thus, investigations to date have not documented a substantial increase in GBS associated with influenza vaccines (other than the swine influenza vaccine in 1976), and that, if influenza vaccine does pose a risk, it is probably slightly more than one additional case/1 million persons vaccinated. Recent data from VAERS has documented decreased reporting of post influenza vaccine GBS across age groups, despite overall increased reporting for influenza vaccine (208). Cases of GBS after influenza infection have been reported, but no epidemiologic studies have documented such an association (209,210). Substantial evidence exists that multiple infectious illnesses, most notably Campylobacter jejuni, and upper respiratory tract infections are associated with GBS (203,(211)(212)(213). Even if GBS were a true side effect of vaccination in the years after 1976, the estimated risk for GBS of approximately 1 additional case/1 million persons vaccinated is substantially less than the risk for severe influenza, which can be prevented by vaccination among all age groups, especially persons aged >65 years and those who have medical indications for influenza vaccination (Table 1) (see Hospitalizations and Deaths from Influenza). The potential benefits of influenza vaccination in preventing serious illness, hospitalization, and death substantially outweigh the possible risks for experiencing vaccine-associated GBS. The average case fatality ratio for GBS is 6% and increases with age (203,214). No evidence indicates that the case fatality ratio for GBS differs among vaccinated persons and those not vaccinated. The incidence of GBS among the general population is low, but persons with a history of GBS have a substantially greater likelihood of subsequently experiencing GBS than persons without such a history (204,215). Thus, the likelihood of coincidentally experiencing GBS after influenza vaccination is expected to be greater among persons with a history of GBS than among persons with no history of this syndrome. Whether influenza vaccination specifically might increase the risk for recurrence of GBS is unknown; therefore, avoiding vaccinating persons who are not at high risk for severe influenza complications and who are known to have experienced GBS within 6 weeks after a previous influenza vaccination is prudent. As an alternative, physicians might consider using influenza an-tiviral chemoprophylaxis for these persons. Although data are limited, for the majority of persons who have a history of GBS and who are at high risk for severe complications from influenza, the established benefits of influenza vaccination justify yearly vaccination. # Live, Attenuated Influenza Vaccine Recommendations Background Description and Action Mechanisms. LAIVs have been in development since the 1960s in the United States, where they have been evaluated as mono-, bi-, and trivalent formulations (216)(217)(218). The LAIV licensed for use in the United States beginning in 2003 is produced by MedImmune, Inc. (Gaithersburg, Maryland; ) and marketed under the name FluMist™. It is a live, trivalent, intranasally administered vaccine that is - attenuated, producing mild or no signs or symptoms related to influenza virus infection; - temperature-sensitive, a property that limits the replication of the vaccine viruses at 38 º C-39 º C, and thus restricts LAIV viruses from replicating efficiently in human lower airways; and - cold-adapted, replicating efficiently at 25 º C, a temperature that is permissive for replication of LAIV viruses, but restrictive for replication of different wild-type viruses. In animal studies, LAIV viruses replicate in the mucosa of the nasopharynx, inducing protective immunity against viruses included in the vaccine, but replicate inefficiently in the lower airways or lungs. The first step in developing an LAIV was the derivation of two stably attenuated master donor viruses (MDV), one for type A and one for type B influenza viruses. The two MDVs each acquired the cold-adapted, temperature-sensitive, attenuated phenotypes through serial passage in viral culture conducted at progressively lower temperatures. The vaccine viruses in LAIV are reassortant viruses containing genes from these MDVs that confer attenuation, temperature sensitivity, and cold adaptation and genes from the recommended contemporary wild-type influenza viruses, encoding the surface antigens hemagglutinin (HA) and neuraminidase (NA). Thus, MDVs provide the stably attenuated vehicles for presenting influenza HA and NA antigens, to which the protective antibody response is directed, to the immune system. The reassortant vaccine viruses are grown in embryonated hens eggs. After the vaccine is formulated and inserted into individual sprayers for nasal administration, the vaccine must be stored at -15 º C or colder. The immunogenicity of the approved LAIV has been assessed in multiple studies (102,(219)(220)(221)(222)(223)(224), which included approximately 100 children aged 5-17 years, and approximately 300 adults aged 18-49 years. LAIV virus strains replicate primarily in nasopharyngeal epithelial cells. The protective mechanisms induced by vaccination with LAIV are not completely understood but appear to involve both serum and nasal secretory antibodies. No single laboratory measurement closely correlates with protective immunity induced by LAIV. Shedding and Transmission of Vaccine Viruses. Available data indicate that both children and adults vaccinated with LAIV can shed vaccine viruses for >2 days after vaccination, although in lower titers than typically occur with shedding of wild-type influenza viruses. Shedding should not be equated with person-to-person transmission of vaccine viruses, although, in rare instances, shed vaccine viruses can be transmitted from vaccinees to nonvaccinated persons. One unpublished study in a child care center settingassessed transmissibility of vaccine viruses from 98 vaccinated to 99 unvaccinated subjects, all aged 8-36 months. Eighty percent of vaccine recipients shed one or more virus strains, with a mean of 7.6 days' duration (225). One vaccine type influenza type B isolate was recovered from a placebo recipient and was confirmed to be vaccine-type virus. The type B isolate retained the cold-adapted, temperature-sensitive, attenuated phenotype, and it possessed the same genetic sequence as a virus shed from a vaccine recipient in the same children's play group. The placebo recipient from whom the influenza type B vaccine virus was isolated did not exhibit symptoms that were different from those experienced by vaccine recipients. The estimated probability of acquiring vaccine virus after close contact with a single LAIV recipient in this child care population was 0.58%-2.4%. One study assessing shedding of vaccine viruses in 20 healthy vaccinated adults aged 18-49 years demonstrated that the majority of shedding occurred within the first 3 days after vaccination, although one subject was noted to shed virus on day 7 after vaccine receipt. No subject shed vaccine viruses >10 days after vaccination. Duration or type of symptoms associated with receipt of LAIV did not correlate with duration of shedding of vaccine viruses. Person-to-person transmission of vaccine viruses was not assessed in this study (226). Another study assessing shedding of vaccine viruses in 14 healthy adults aged 18-49 years indicated that 50% of these adults had viral antigen detected by direct immunofluorescence or rapid antigen tests within 7 days of vaccination. Most viral shedding was detected on day 2 or 3. Person-to-person transmission of vaccine viruses was not assessed in this study (227). # Stability of Vaccine Viruses. In clinical trials, viruses shed by vaccine recipients have been phenotypically stable. In one study, nasal and throat swab specimens were collected from 17 study participants for 2 weeks after vaccine receipt (228). Virus isolates were analyzed by multiple genetic techniques. All isolates retained the LAIV genotype after replication in the human host, and all retained the cold-adapted and temperature-sensitive phenotypes. # Using LAIV LAIV is an option for vaccination of healthy persons aged 5-49 years, including health-care workers and other persons in close contact with groups at high risk and those wanting to avoid influenza. During periods when inactivated vaccine is in short supply, use of LAIV is encouraged when feasible for eligible persons (including health-care workers) because use of LAIV by these persons might increase availability of inactivated vaccine for persons in groups at high risk. Possible advantages of LAIV include its potential to induce a broad mucosal and systemic immune response, its ease of administration, and the acceptability of an intranasal rather than intramuscular route of administration. # Persons Who Should Not Be Vaccinated with LAIV The following populations should not be vaccinated with LAIV: # Close Contacts of Persons at High Risk for Complications from Influenza Close contacts of persons at high risk for complications from influenza should receive influenza vaccine to reduce transmission of wild-type influenza viruses to persons at high risk. ACIP has not indicated a preference for inactivated influenza vaccine use by health-care workers or other persons who have close contact with persons with lesser degrees of immunosuppression (e.g., persons with diabetes, persons with asthma taking corticosteroids, or persons infected with HIV) or for inactivated influenza vaccine use by health-care workers or other healthy persons aged 5-49 years in close contact with all other groups at high risk. Use of inactivated influenza vaccine is preferred for vaccinating household members, healthcare workers, and others who have close contact with severely immunosuppressed persons (e.g., patients with hematopoietic stem cell transplants) during those periods in which the immunosuppressed person requires care in a protective environment. The rationale for not using LAIV among healthcare workers caring for such patients is the theoretical risk that a live, attenuated vaccine virus could be transmitted to the severely immunosuppressed person. If a health-care worker receives LAIV, that worker should refrain from contact with severely immunosuppressed patients for 7 days after vaccine receipt. Hospital visitors who have received LAIV should refrain from contact with severely immunosuppressed persons for 7 days after vaccination; however, such persons need not be excluded from visitation of patients who are not severely immunosuppressed. # Personnel Who May Administer LAIV Low-level introduction of vaccine viruses into the environment is likely unavoidable when administering LAIV. The risk for acquiring vaccine viruses from the environment is unknown but likely to be limited. Severely immunosuppressed persons should not administer LAIV. However, other persons at high risk for influenza complications may administer LAIV. These include persons with underlying medical conditions placing them at high risk or who are likely to be at risk, including pregnant women, persons with asthma, and persons aged >50 years. # LAIV Dosage and Administration LAIV is intended for intranasal administration only and should not be administered by the intramuscular, intradermal, or intravenous route. LAIV must be thawed before administration. This can be accomplished by holding an individual sprayer in the palm of the hand until thawed, with subsequent immediate administration. Alternatively, the vaccine can be thawed in a refrigerator and stored at 2 º C-8 º C for <24 hours before use. Vaccine should not be refrozen after thawing. LAIV is supplied in a prefilled single-use sprayer containing 0.5 mL of vaccine. Approximately 0.25 mL (i.e., half of the total sprayer contents) is sprayed into the first nostril while the recipient is in the upright position. An attached dose-divider clip is removed from the sprayer to administer the second half of the dose into the other nostril. If the vaccine recipient sneezes after administration, the dose should not be repeated. LAIV should be administered annually according to the following schedule: - Children aged 5-8 years previously unvaccinated at any time with either LAIV or inactivated influenza vaccine should receive 2 doses † of LAIV separated by 6-10 weeks. - Children aged 5-8 years previously vaccinated at any time with either LAIV or inactivated influenza vaccine should receive 1 dose of LAIV. They do not require a second dose. - Persons aged 9-49 years should receive 1 dose of LAIV. LAIV can be administered to persons with minor acute illnesses (e.g., diarrhea or mild upper respiratory tract infection with or without fever). However, if clinical judgment indicates nasal congestion is present that might impede delivery of the vaccine to the nasopharyngeal mucosa, deferral of administration should be considered until resolution of the illness. Whether concurrent administration of LAIV with other vaccines affects the safety or efficacy of either LAIV or the simultaneously administered vaccine is unknown. In the absence of specific data indicating interference, following the ACIP general recommendations for immunization is prudent (67). Inactivated vaccines do not interfere with the immune response to other inactivated vaccines or to live vaccines. An inactivated vaccine can be administered either simultaneously or at any time before or after LAIV. Two live vaccines not administered on the same day should be administered >4 weeks apart when possible. # LAIV and Use of Influenza Antiviral Medications The effect on safety and efficacy of LAIV coadministration with influenza antiviral medications has not been studied. However, because influenza antivirals reduce replication of influenza viruses, LAIV should not be administered until 48 hours after cessation of influenza antiviral therapy, and influenza antiviral medications should not be administered for 2 weeks after receipt of LAIV. # LAIV Storage LAIV must be stored at -15 º C or colder. A manufacturersupplied freezer box was formerly required for storage of LAIV in a frost-free freezer; however, the freezer box is now optional, and LAIV may now be stored in frost-free freezers without using a freezer box. LAIV can be thawed in a refrigerator and stored at 2 º C-8 º C for <60 hours before use. It should not be refrozen after thawing. # Side Effects and Adverse Reactions Twenty prelicensure clinical trials assessed the safety of the approved LAIV. In these combined studies, approximately 28,000 doses of the vaccine were administered to approximately 20,000 subjects. A subset of these trials were randomized, placebo-controlled studies in which an estimated 4,000 healthy children aged 5-17 years and 2,000 healthy adults aged 18-49 years were vaccinated. The incidence of adverse events possibly complicating influenza (e.g., pneumonia, bronchitis, bronchiolitis, or central nervous system events) was not statistically different among LAIV and placebo recipients aged 5-49 years. LAIV is made from attenuated viruses and does not cause influenza in vaccine recipients. Children. In a subset of healthy children aged 60-71 months from one clinical trial (97,98), certain signs and symptoms were reported more often among LAIV recipients after the first dose (n = 214) than placebo recipients (n = 95) (e.g., runny nose, 48.1% versus 44.2%; headache, 17.8% versus 11.6%; vomiting, 4.7% versus 3.2%; and myalgias, 6.1% versus 4.2%), but these differences were not statistically significant. In other trials, signs and symptoms reported after LAIV administration have included runny nose or nasal congestion (20%-75%), headache (2%-46%), fever (0%-26%), vomiting (3%-13%), abdominal pain (2%), and myalgias (0%-21%) (219,222,224,(229)(230)(231). These symptoms were associated more often with the first dose and were self-limited. Unpublished data from a study including subjects aged 1-17 years indicated an increase in asthma or reactive airways disease in the subset aged 12-59 months. Because of this, LAIV is not approved for use among children aged <60 months. Adults. Among adults, runny nose or nasal congestion (28%-78%), headache (16%-44%), and sore throat (15%-27%) have been reported more often among vaccine recipients than placebo recipients (100,232,233). In one clinical trial (100) among a subset of healthy adults aged 18-49 years, signs and symptoms reported more frequently among LAIV recipients (n = 2,548) than placebo recipients (n = 1,290) within 7 days after each dose included cough (13.9% versus 10.8%); runny nose (44.5% versus 27.1%); sore throat (27.8% versus 17.1%); chills (8.6% versus 6.0%); and tiredness/ weakness (25.7% versus 21.6%). Safety Among Groups at High Risk from Influenza-Related Morbidity. Until additional data are acquired and analyzed, persons at high risk for experiencing complications from influenza infection (e.g., immunocompromised patients; patients with asthma, cystic fibrosis, or chronic obstructive pulmonary disease; or persons aged >65 years) should not be vaccinated with LAIV. Protection from influenza among these groups should be accomplished by using inactivated influenza vaccine. Serious Adverse Events. Serious adverse events among healthy children aged 5-17 years or healthy adults aged 18-49 years occurred at a rate of <1%. Surveillance should continue for adverse events that might not have been detected in previous studies. A preliminary review of reports to VAERS after distribution of approximately 800,000 doses during the 2003-04 influenza season did not reveal any substantial new safety concerns (234). Health-care professionals should promptly report all clinically significant adverse events after LAIV administration to VAERS, as recommended for inactivated influenza vaccine. # Recommended Vaccines for Different Age Groups When vaccinating children aged 6 months-3 years, healthcare providers should use inactivated influenza vaccine that has been approved by FDA for this age group. Inactivated influenza vaccine from Sanofi Pasteur, Inc., (FluZone splitvirus) is approved for use among persons aged >6 months. Inactivated influenza vaccine from Chiron (Fluvirin) is labeled in the United States for use among persons aged >4 years because data to demonstrate efficacy among younger persons have not been provided to FDA. Live, attenuated influenza vaccine from MedImmune (FluMist) is approved for use by healthy persons aged 5-49 years (Table 5). # Timing of Annual Influenza Vaccination The annual supply of influenza vaccine and the timing of its distribution cannot be guaranteed in any year. Information regarding the supply of 2005-06 vaccine might not be available until late summer or early fall 2005. To allow vaccine providers to plan for the upcoming vaccination season, taking into account the yearly possibility of vaccine delays or shortages and the need to ensure vaccination of persons at high risk and their contacts, ACIP recommends that inactivated influenza vaccine campaigns conducted in October focus primarily on persons at increased risk for influenza complications and their contacts, including health-care workers. Campaigns conducted in November and later should continue to vaccinate persons at high risk and their contacts, but also vaccinate other persons who wish to decrease their risk for influenza infection. Vaccination for all groups should continue into December and beyond. CDC and other public health agencies will assess the vaccine supply on a continuing basis throughout the manufacturing period and will make recommendations preceding the 2005-06 influenza season regarding the need for tiered timing of inactivated influenza vaccination of different risk groups. Because LAIV is approved for use in healthy persons 5-49 years, its use has not been subject to tiered timing. # Vaccination Before October To avoid missed opportunities for vaccination of persons at high risk for serious complications, such persons should be offered vaccine beginning in September during routine healthcare visits or during hospitalizations, if vaccine is available. In facilities housing older persons (e.g., nursing homes), vaccination before October typically should be avoided because antibody levels in such persons can begin to decline within a limited time after vaccination (235). In addition, children aged <9 years who have not been previously vaccinated and who need 2 doses before the start of the influenza season can receive their first dose in September so that both doses of the most up-to-date vaccine can be administered before the onset of influenza activity. For previously vaccinated children, 2 doses are needed to provide optimal protection against influenza. # Vaccination in October and November The optimal time to vaccinate is usually during October-November. ACIP recommends that vaccine providers focus their vaccination efforts in October and earlier primarily on persons aged >50 years, persons aged <50 years at increased risk for influenza-related complications (including children aged 6-23 months), household contacts of persons at high risk (including out-of-home caregivers and household contacts of children aged 0-23 months), and health-care workers. Vaccination of children aged <9 years who are receiving vaccine for the first time should also begin in October or earlier because those persons need a booster dose 1 month after the initial dose. Efforts to vaccinate other persons who wish to decrease their risk for influenza infection should begin in November; however, if such persons request vaccination in October, vaccination should not be deferred, unless vaccine supplies dictate otherwise. Materials to assist providers in prioritizing early vaccine are available at / professionals/vaccination/index.htm (see also Travelers in this report). # Timing of Organized Vaccination Campaigns Persons and institutions planning substantial organized vaccination campaigns should consider scheduling these events after mid-October because the availability of vaccine in any location cannot be ensured consistently in early fall. Scheduling campaigns after mid-October will minimize the need for cancellations because vaccine is unavailable. Campaigns conducted before November using inactivated vaccine should focus efforts on vaccination of persons aged >50 years, persons aged <50 years at increased risk for influenza-related complications (including children aged 6-23 months and pregnant women), health-care workers, and household contacts of persons at high-risk (including children aged 0-23 months) to the extent feasible. Campaigns using the LAIV are also optimally conducted in October and November. # Vaccination in December and Later After November, many persons who should or want to receive influenza vaccine remain unvaccinated. In addition, substantial amounts of vaccine are often left over at the end of the influenza season. To improve vaccine coverage, influenza vaccine should continue to be offered in December and throughout the influenza season as long as vaccine supplies are available, even after influenza activity has been documented in the community. In the United States, seasonal influenza activity can begin to increase as early as October or November, but influenza activity has not reached peak levels in the majority of recent seasons until late December-early March (Table 6). Therefore, although the timing of influenza activity can vary by region, vaccine administered after November is likely to be beneficial in the majority of influenza seasons. Adults develop peak antibody protection against influenza infection 2 weeks after vaccination (236,237). # Strategies for Implementing Vaccination Recommendations in Health-Care Settings Successful vaccination programs combine publicity and education for health-care workers and other potential vaccine recipients, a plan for identifying persons at high risk, use of reminder/recall systems, assessment of practice-level vaccination rates with feedback to staff, and efforts to remove administrative and financial barriers that prevent persons from receiving the vaccine, including use of standing orders programs (19,238). Using standing orders programs is recommended for long-term-care facilities (e.g., nursing homes and skilled nursing facilities), hospitals, and home health agencies to ensure the administration of recommended vaccinations for adults (239). Standing orders programs for both influenza and pneumococcal vaccination should be conducted under the supervision of a licensed practitioner according to a physician-approved facility or agency policy by health-care workers trained to screen patients for contraindications to vaccination, administer vaccine, and monitor for adverse events. The Centers for Medicare and Medicaid Services (CMS) has removed the physician signature requirement for the administration of influenza and pneumococcal vaccines to Medicare and Medicaid patients in hospitals, long-term-care facilities, and home health agencies (239). To the extent allowed by local and state law, these facilities and agencies may implement standing orders for influenza and pneumococcal vaccination of Medicare-and Medicaid-eligible patients. Other settings (e.g., outpatient facilities, managed care organizations, assisted living facilities, correctional facilities, pharmacies, and adult workplaces) are encouraged to introduce standing orders programs as well (20). In addition, physician reminders (e.g., flagging charts) and patient reminders are recommended strategies for increasing rates of influenza vaccination. Persons for whom influenza vaccine is recommended can be identified and vaccinated in the settings described in the following sections. # Outpatient Facilities Providing Ongoing Care Staff in facilities providing ongoing medical care (e.g., physicians' offices, public health clinics, employee health clinics, hemodialysis centers, hospital specialty-care clinics, and outpatient rehabilitation programs) should identify and label the medical records of patients who should receive vaccination. Vaccine should be offered during visits beginning in Septem-ber and throughout the influenza season. The offer of vaccination and its receipt or refusal should be documented in the medical record. Patients for whom vaccination is recommended and who do not have regularly scheduled visits during the fall should be reminded by mail, telephone, or other means of the need for vaccination. # Outpatient Facilities Providing Episodic or Acute Care Beginning each September, acute health-care facilities (e.g., emergency departments and walk-in clinics) should offer vaccinations to persons for whom vaccination is recommended or provide written information regarding why, where, and how to obtain the vaccine. This written information should be available in languages appropriate for the populations served by the facility. # Nursing Homes and Other Residential Long-Term-Care Facilities During October and November each year, vaccination should be routinely provided to all residents of chronic-care facilities with the concurrence of attending physicians. Consent for vaccination should be obtained from the resident or a family member at the time of admission to the facility or anytime afterwards. All residents should be vaccinated at one time, preceding the influenza season. Residents admitted through March after completion of the vaccination program at the facility should be vaccinated at the time of admission. # Acute-Care Hospitals Persons of all ages (including children) with high-risk conditions and persons aged >50 years who are hospitalized at any time during September-March should be offered and strongly encouraged to receive influenza vaccine before they are discharged. In one study, 39%-46% of adult patients hospitalized during the winter with influenza-related diagnoses had been hospitalized during the preceding autumn (240). Thus, the hospital serves as a setting in which persons at increased risk for subsequent hospitalization can be identified and vaccinated. However, vaccination of persons at high risk during or after their hospitalizations is often not done. In a study of hospitalized Medicare patients, only 31.6% were vaccinated before admission, 1.9% during admission, and 10.6% after admission (241). Using standing orders in hospitals increases vaccination rates among hospitalized persons (242). # Visiting Nurses and Others Providing Home Care to Persons at High Risk Beginning in September, nursing-care plans should identify patients for whom vaccination is recommended, and vac-cine should be administered in the home, if necessary. Caregivers and other persons in the household (including children) should be referred for vaccination. # Other Facilities Providing Services to Persons Aged >50 Years Beginning in October, such facilities as assisted living housing, retirement communities, and recreation centers should offer unvaccinated residents and attendees vaccination on-site before the influenza season. Staff education should emphasize the need for influenza vaccine. # Health-Care Workers Beginning in October each year, health-care facilities should offer influenza vaccinations to all workers, including night and weekend staff. Particular emphasis should be placed on providing vaccinations to persons who care for members of groups at high risk. Efforts should be made to educate healthcare workers regarding the benefits of vaccination and the potential health consequences of influenza illness for themselves, their family members, and their patients. All healthcare workers should be provided convenient access to influenza vaccine at the work site, free of charge, as part of employee health programs (127,137). # Influenza Vaccine Supply Influenza vaccine distribution delays or vaccine supply shortages have occurred in the United States vaccine in three of the last five influenza seasons. Influenza vaccine delivery delays or vaccine shortages remain possible in part because of the inherent critical time constraints in manufacturing the vaccine given the annual updating of the influenza vaccine strains. Steps being taken to accommodate possible future delays or vaccine shortages include identification and implementation of ways to expand the influenza vaccine supply and improvement of targeted delivery of vaccine to groups at high risk when delays or shortages are expected. # Influenza Vaccine Use During Shortages of Inactivated Vaccine ACIP will publish additional guidance regarding the prioritized (tiered) use of inactivated influenza vaccine to be implemented only during periods when there is a shortage of influenza vaccine. Otherwise, when vaccine is in adequate supply, every effort should be made to promote and use influenza vaccine for all regularly targeted groups and for other persons who wish to reduce their risk for influenza illness. The prioritized (tiered) use of influenza vaccine during inactivated influenza vaccine shortages applies only to use of inactivated vaccine and not to LAIV. When feasible, during shortages of inactivated influenza vaccine, LAIV should be used preferentially for all healthy persons aged 5-49 years (including health-care workers) to increase the availability of inactivated vaccine for groups at high risk. # Future Directions for Influenza Vaccine Recommendations ACIP plans to review new vaccination strategies for improving prevention and control of influenza, including the possibility of expanding recommendations for use of influenza vaccines. In addition, strategies for regularly monitoring vaccine effectiveness will be reviewed. # Recommendations for Using Antiviral Agents for Influenza Antiviral drugs for influenza are an adjunct to influenza vaccine for controlling and preventing influenza. However, these agents are not a substitute for vaccination. Four licensed influenza antiviral agents are available in the United States: amantadine, rimantadine, zanamivir, and oseltamivir. Amantadine and rimantadine are chemically related antiviral drugs known as adamantanes with activity against influenza A viruses, but not influenza B viruses. Amantadine was approved in 1966 for chemoprophylaxis of influenza A (H2N2) infection and was later approved in 1976 for treatment and chemoprophylaxis of influenza type A virus infections among adults and children aged >1 year. Rimantadine was approved in 1993 for treatment and chemoprophylaxis of influenza A infection among adults and prophylaxis among children. Although rimantadine is approved only for chemoprophylaxis of influenza A infection among children, rimantadine treatment for influenza A among children can be beneficial (243). Zanamivir and oseltamivir are chemically related antiviral drugs known as neuraminidase inhibitors that have activity against both influenza A and B viruses. Both zanamivir and oseltamivir were approved in 1999 for treating uncomplicated influenza infections. Zanamivir is approved for treating persons aged >7 years, and oseltamivir is approved for treatment of persons aged >1 year. In 2000, oseltamivir was approved for chemoprophylaxis of influenza among persons aged >13 years. The four drugs differ in pharmacokinetics, side effects, routes of administration, approved age groups, dosages, and costs. An overview of the indications, use, administration, and known primary side effects of these medications is presented in the following sections. Information contained in this report might not represent FDA approval or approved labeling for the anti-viral agents described. Package inserts should be consulted for additional information. # Role of Laboratory Diagnosis Appropriate treatment of patients with respiratory illness depends on accurate and timely diagnosis. Early diagnosis of influenza can reduce the inappropriate use of antibiotics and provide the option of using antiviral therapy. However, because certain bacterial infections can produce symptoms similar to influenza, bacterial infections should be considered and appropriately treated, if suspected. In addition, bacterial infections can occur as a complication of influenza. Influenza surveillance information and diagnostic testing can aid clinical judgment and help guide treatment decisions. The accuracy of clinical diagnosis of influenza on the basis of symptoms alone is limited because symptoms from illness caused by other pathogens can overlap considerably with influenza (30,34,35). Influenza surveillance by state and local health departments and CDC can provide information regarding the presence of influenza viruses in the community. Surveillance can also identify the predominant circulating types, influenza A subtypes, and strains of influenza. Diagnostic tests available for influenza include viral culture, serology, rapid antigen testing, polymerase chain reaction (PCR), and immunofluorescence assays (25). Sensitivity and specificity of any test for influenza might vary by the laboratory that performs the test, the type of test used, and the type of specimen tested. Among respiratory specimens for viral isolation or rapid detection, nasopharyngeal specimens are typically more effective than throat swab specimens (244). As with any diagnostic test, results should be evaluated in the context of other clinical and epidemiologic information available to health-care providers. Commercial rapid diagnostic tests are available that can detect influenza viruses within 30 minutes (25,245). Some tests are approved for use in any outpatient setting, whereas others must be used in a moderately complex clinical laboratory. These rapid tests differ in the types of influenza viruses they can detect and whether they can distinguish between influenza types. Different tests can detect 1) only influenza A viruses; 2) both influenza A and B viruses, but not distinguish between the two types; or 3) both influenza A and B and distinguish between the two. None of the tests provide any information about influenza A subtypes. The types of specimens acceptable for use (i.e., throat, nasopharyngeal, or nasal aspirates, swabs, or washes) also vary by test. The specificity and, in particular, the sensitivity of rapid tests are lower than for viral culture and vary by test (246,247). Because of the lower sensitivity of the rapid tests, physicians should consider confirming negative tests with viral culture or other means because of the possibility of falsenegative rapid test results, especially during periods of peak community influenza activity. In contrast, false-positive rapid test results are less likely, but can occur during periods of low influenza activity. Therefore, when interpreting results of a rapid influenza test, physicians should consider the positive and negative predictive values of the test in the context of the level of influenza activity in their community. Package inserts and the laboratory performing the test should be consulted for more details regarding use of rapid diagnostic tests. Additional information concerning diagnostic testing is available at . Despite the availability of rapid diagnostic tests, collecting clinical specimens for viral culture is critical, because only culture isolates can provide specific information regarding circulating strains and subtypes of influenza viruses. This information is needed to compare current circulating influenza strains with vaccine strains, to guide decisions regarding influenza treatment and chemoprophylaxis, and to formulate vaccine for the coming year. Virus isolates also are needed to monitor the emergence of antiviral resistance and the emergence of novel influenza A subtypes that might pose a pandemic threat. # Indications for Use Treatment When administered within 2 days of illness onset to otherwise healthy adults, amantadine and rimantadine can reduce the duration of uncomplicated influenza A illness, and zanamivir and oseltamivir can reduce the duration of uncomplicated influenza A and B illness by approximately 1 day, compared with placebo (75,(248)(249)(250)(251)(252)(253)(254)(255)(256)(257)(258)(259)(260)(261)(262)(263)(264)(265). More clinical data are available concerning the efficacy of zanamivir and oseltamivir for treatment of influenza A infection than for treatment of influenza B infection (253,(266)(267)(268)(269)(270)(271)(272)(273)(274)(275)(276)(277)(278)(279)(280)(281). However, in vitro data and studies of treatment among mice and ferrets (282)(283)(284)(285)(286)(287)(288)(289), in addition to clinical studies, have documented that zanamivir and oseltamivir have activity against influenza B viruses (254,(258)(259)(260)290,291). Data are limited regarding the effectiveness of the four antiviral agents in preventing serious influenza-related complications (e.g., bacterial or viral pneumonia or exacerbation of chronic diseases). Evidence for the effectiveness of these four antiviral drugs is principally based on studies of patients with uncomplicated influenza (292). Data are limited and inconclusive concerning the effectiveness of amantadine, rimantadine, zanamivir, and oseltamivir for treatment of influenza among persons at high risk for serious complications of influenza (28,248,250,251,253,254,261,(266)(267)(268)(269)(270). One study assessing oseltamivir treatment primarily among adults reported a reduction in complications, necessitating antibiotic therapy compared with placebo (271). Fewer studies of the efficacy of influenza antivirals have been conducted among pediatric populations (248,251,257,258,267,272,273). One study of oseltamivir treatment documented a decreased incidence of otitis media among children (258). Inadequate data exist regarding the safety and efficacy of any of the influenza antiviral drugs for use among children aged <1 year (247). To reduce the emergence of antiviral drug-resistant viruses, amantadine or rimantadine therapy for persons with influenza A illness should be discontinued as soon as clinically warranted, typically after 3-5 days of treatment or within 24-48 hours after the disappearance of signs and symptoms. The recommended duration of treatment with either zanamivir or oseltamivir is 5 days. # Chemoprophylaxis Chemoprophylactic drugs are not a substitute for vaccination, although they are critical adjuncts in preventing and controlling influenza. Both amantadine and rimantadine are indicated for chemoprophylaxis of influenza A infection, but not influenza B. Both drugs are approximately 60%-90% effective in preventing illness from influenza A infection (75,248,267). When used as prophylaxis, these antiviral agents can prevent illness while permitting subclinical infection and development of protective antibody against circulating influenza viruses. Therefore, certain persons who take these drugs will develop protective immune responses to circulating influenza viruses. Amantadine and rimantadine do not interfere with the antibody response to the vaccine (248). Both drugs have been studied extensively among nursing home populations as a component of influenza outbreak-control programs, which can limit the spread of influenza within chronic-care institutions (248,266,(274)(275)(276). Among the neuraminidase inhibitor antivirals zanamivir and oseltamivir, only oseltamivir has been approved for prophylaxis, but community studies of healthy adults indicate that both drugs are similarly effective in preventing febrile, laboratory-confirmed influenza illness (efficacy: zanamivir, 84%; oseltamivir, 82%) (253,277,293). Both antiviral agents have also been reported to prevent influenza illness among persons administered chemoprophylaxis after a household member had influenza diagnosed (278,290,293). Experience with prophylactic use of these agents in institutional settings or among patients with chronic medical conditions is limited in comparison with the adamantanes (260,269,270,(279)(280)(281). One 6-week study of oseltamivir prophylaxis among nursing home residents reported a 92% reduction in influenza illness (260,294). Use of zanamivir has not been reported to impair the immunologic response to influenza vaccine (259,295). Data are not available regarding the efficacy of any of the four antiviral agents in preventing influenza among severely immunocompromised persons. When determining the timing and duration for administering influenza antiviral medications for prophylaxis, factors related to cost, compliance, and potential side effects should be considered. To be maximally effective as prophylaxis, the drug must be taken each day for the duration of influenza activity in the community. However, to be most cost-effective, one study of amantadine or rimantadine prophylaxis reported that the drugs should be taken only during the period of peak influenza activity in a community (296). Persons at High Risk Who Are Vaccinated After Influenza Activity Has Begun. Persons at high risk for complications of influenza still can be vaccinated after an outbreak of influenza has begun in a community. However, development of antibodies in adults after vaccination takes approximately 2 weeks (236,237). When influenza vaccine is administered while influenza viruses are circulating, chemoprophylaxis should be considered for persons at high risk during the time from vaccination until immunity has developed. Children aged <9 years who receive influenza vaccine for the first time can require 6 weeks of prophylaxis (i.e., prophylaxis for 4 weeks after the first dose of vaccine and an additional 2 weeks of prophylaxis after the second dose). Persons Who Provide Care to Those at High Risk. To reduce the spread of virus to persons at high risk during community or institutional outbreaks, chemoprophylaxis during peak influenza activity can be considered for unvaccinated persons who have frequent contact with persons at high risk. Persons with frequent contact include employees of hospitals, clinics, and chronic-care facilities, household members, visiting nurses, and volunteer workers. If an outbreak is caused by a variant strain of influenza that might not be controlled by the vaccine, chemoprophylaxis should be considered for all such persons, regardless of their vaccination status. Persons Who Have Immune Deficiencies. Chemoprophylaxis can be considered for persons at high risk who are expected to have an inadequate antibody response to influenza vaccine. This category includes persons infected with HIV, chiefly those with advanced HIV disease. No published data are available concerning possible efficacy of chemoprophylaxis among persons with HIV infection or interactions with other drugs used to manage HIV infection. Such patients should be monitored closely if chemoprophylaxis is administered. Other Persons. Chemoprophylaxis throughout the influenza season or during peak influenza activity might be appropriate for persons at high risk who should not be vaccinated. Chemoprophylaxis can also be offered to persons who wish to avoid influenza illness. Health-care providers and patients should make this decision on an individual basis. # Control of Influenza Outbreaks in Institutions Using antiviral drugs for treatment and prophylaxis of influenza is a key component of influenza outbreak control in institutions. In addition to antiviral medications, other outbreak-control measures include instituting droplet precautions and establishing cohorts of patients with confirmed or suspected influenza, re-offering influenza vaccinations to unvaccinated staff and patients, restricting staff movement between wards or buildings, and restricting contact between ill staff or visitors and patients (297-299) (for additional information regarding outbreak control in specific settings, see Additional Information Regarding Influenza Infection Control Among Specific Populations). The majority of published reports concerning use of antiviral agents to control influenza outbreaks in institutions are based on studies of influenza A outbreaks among nursing home populations where amantadine or rimantadine were used (248,266,(274)(275)(276)296). Less information is available concerning use of neuraminidase inhibitors in influenza A or B institutional outbreaks (269,270,281,294,300). When confirmed or suspected outbreaks of influenza occur in institutions that house persons at high risk, chemoprophylaxis should be started as early as possible to reduce the spread of the virus. In these situations, having preapproved orders from physicians or plans to obtain orders for antiviral medications on short notice can substantially expedite administration of antiviral medications. When outbreaks occur in institutions, chemoprophylaxis should be administered to all residents, regardless of whether they received influenza vaccinations during the previous fall, and should continue for a minimum of 2 weeks. If surveillance indicates that new cases continue to occur, chemoprophylaxis should be continued until approximately 1 week after the end of the outbreak. The dosage for each resident should be determined individually. Chemoprophylaxis also can be offered to unvaccinated staff who provide care to persons at high risk. Prophylaxis should be considered for all employees, regardless of their vaccination status, if the outbreak is caused by a variant strain of influenza that is not well-matched by the vaccine. In addition to nursing homes, chemoprophylaxis also can be considered for controlling influenza outbreaks in other closed or semiclosed settings (e.g., dormitories or other settings in which persons live in close proximity). For example, chemoprophylaxis with rimantadine has been used successfully to control an influenza A outbreak aboard a large cruise ship (177). To limit the potential transmission of drug-resistant virus during outbreaks in institutions, whether in chronic or acutecare settings or other closed settings, measures should be taken to reduce contact as much as possible between persons taking antiviral drugs for treatment and other persons, including those taking chemoprophylaxis (see Antiviral Drug-Resistant Strains of Influenza). # Dosage Dosage recommendations vary by age group and medical conditions (Table 7). # Children Amantadine. Use of amantadine among children aged 10 years is 200 mg/ day (100 mg twice a day); however, for children weighing <40 kg, prescribing 5 mg/kg body weight/day, regardless of age, is advisable (268). Rimantadine. Rimantadine is approved for prophylaxis among children aged >1 year and for treatment and prophylaxis among adults. Although rimantadine is approved only for prophylaxis of infection among children, certain specialists in the management of influenza consider it appropriate for treatment among children (243). Use of rimantadine among children aged 10 years is 200 mg/day (100 mg twice a day); however, for children weighing <40 kg, prescribing 5 mg/kg body weight/day, regardless of age, is recommended (301). Zanamivir. Zanamivir is approved for treatment among children aged >7 years. The recommended dosage of zanamivir for treatment of influenza is two inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) twice daily (approximately 12 hours apart) (259). Oseltamivir. Oseltamivir is approved for treatment among persons aged >1 year and for chemoprophylaxis among persons aged >13 years. Recommended treatment dosages for children vary by the weight of the child: the dosage recommendation for children who weigh 15-23 kg, the dosage is 45 mg (243). ¶ ¶ Older nursing-home residents should be administered only 100 mg/day of rimantadine. A reduction in dosage to 100 mg/day should be considered for all persons aged >65 years, if they experience possible side effects when taking 200 mg/day. * Zanamivir administered through inhalation by using a plastic device included in the medication package. Patients will benefit from instruction and demonstration of the correct use of the device. † † † Zanamivir is not approved for prophylaxis. § § § A reduction in the dose of oseltamivir is recommended for persons with creatinine clearance 15-23 kg, the dose is 45 mg twice a day. For children who weigh >23-40 kg, the dose is 60 mg twice a day. And, for children who weigh >40 kg, the dose is 75 mg twice a day. twice a day; for those weighing >23-40 kg, the dosage is 60 mg twice a day; and for children weighing >40 kg, the dosage is 75 mg twice a day. The treatment dosage for persons aged >13 years is 75 mg twice daily. For children aged >13 years, the recommended dose for prophylaxis is 75 mg once a day (260). # Persons Aged >65 Years Amantadine. The daily dosage of amantadine for persons aged >65 years should not exceed 100 mg for prophylaxis or treatment, because renal function declines with increasing age. For certain older persons, the dose should be further reduced. Rimantadine. Among older persons, the incidence and severity of central nervous system (CNS) side effects are substantially lower among those taking rimantadine at a dosage of 100 mg/day than among those taking amantadine at dosages adjusted for estimated renal clearance (302). However, chronically ill older persons have had a higher incidence of CNS and gastrointestinal symptoms and serum concentrations 2-4 times higher than among healthy, younger persons when rimantadine has been administered at a dosage of 200 mg/day (248). For prophylaxis among persons aged >65 years, the recommended dosage is 100 mg/day. For treatment of older persons in the community, a reduction in dosage to 100 mg/day should be considered if they experience side effects when taking a dosage of 200 mg/day. For treatment of older nursing home residents, the dosage of rimantadine should be reduced to 100 mg/day (301). Zanamivir and Oseltamivir. No reduction in dosage is recommended on the basis of age alone. # Persons with Impaired Renal Function Amantadine. A reduction in dosage is recommended for patients with creatinine clearance <50 mL/min. Guidelines for amantadine dosage on the basis of creatinine clearance are located in the package insert. Because recommended dosages on the basis of creatinine clearance might provide only an approximation of the optimal dose for a given patient, such persons should be observed carefully for adverse reactions. If necessary, further reduction in the dose or discontinuation of the drug might be indicated because of side effects. Hemodialysis contributes minimally to amantadine clearance (303,304). Rimantadine. A reduction in dosage to 100 mg/day is recommended for persons with creatinine clearance <10 mL/min. Because of the potential for accumulation of rimantadine and its metabolites, patients with any degree of renal insufficiency, including older persons, should be monitored for adverse effects, and either the dosage should be reduced or the drug should be discontinued, if necessary. Hemodialysis contributes minimally to drug clearance (305). Zanamivir. Limited data are available regarding the safety and efficacy of zanamivir for patients with impaired renal function. Among patients with renal failure who were administered a single intravenous dose of zanamivir, decreases in renal clearance, increases in half-life, and increased systemic exposure to zanamivir were observed (259,306). However, a limited number of healthy volunteers who were administered high doses of intravenous zanamivir tolerated systemic levels of zanamivir that were substantially higher than those resulting from administration of zanamivir by oral inhalation at the recommended dose (307,308). On the basis of these considerations, the manufacturer recommends no dose adjustment for inhaled zanamivir for a 5-day course of treatment for patients with either mild-to-moderate or severe impairment in renal function (259). Oseltamivir. Serum concentrations of oseltamivir carboxylate (GS4071), the active metabolite of oseltamivir, increase with declining renal function (260,309). For patients with creatinine clearance of 10-30 mL/min (260), a reduction of the treatment dosage of oseltamivir to 75 mg once daily and in the prophylaxis dosage to 75 mg every other day is recommended. No treatment or prophylaxis dosing recommendations are available for patients undergoing routine renal dialysis treatment. # Persons with Liver Disease Amantadine. No increase in adverse reactions to amantadine has been observed among persons with liver disease. Rare instances of reversible elevation of liver enzymes among patients receiving amantadine have been reported, although a specific relation between the drug and such changes has not been established (310). Rimantadine. A reduction in dosage to 100 mg/day is recommended for persons with severe hepatic dysfunction. Zanamivir and Oseltamivir. Neither of these medications has been studied among persons with hepatic dysfunction. # Persons with Seizure Disorders Amantadine. An increased incidence of seizures has been reported among patients with a history of seizure disorders who have received amantadine (311). Patients with seizure disorders should be observed closely for possible increased seizure activity when taking amantadine. Rimantadine. Seizures (or seizure-like activity) have been reported among persons with a history of seizures who were not receiving anticonvulsant medication while taking rimantadine (312). The extent to which rimantadine might increase the incidence of seizures among persons with seizure disorders has not been adequately evaluated. Zanamivir and Oseltamivir. Seizure events have been reported during postmarketing use of zanamivir and oseltamivir, although no epidemiologic studies have reported any increased risk for seizures with either zanamivir or oseltamivir use. # Route Amantadine, rimantadine, and oseltamivir are administered orally. Amantadine and rimantadine are available in tablet or syrup form, and oseltamivir is available in capsule or oral suspension form. Zanamivir is available as a dry powder that is self-administered via oral inhalation by using a plastic device included in the package with the medication. Patients will benefit from instruction and demonstration of correct use of this device. # Pharmacokinetics Amantadine Approximately 90% of amantadine is excreted unchanged in the urine by glomerular filtration and tubular secretion (274,(313)(314)(315)(316). Thus, renal clearance of amantadine is reduced substantially among persons with renal insufficiency, and dosages might need to be decreased (see Dosage) (Table 7). # Rimantadine Approximately 75% of rimantadine is metabolized by the liver (267). The safety and pharmacokinetics of rimantadine among persons with liver disease have been evaluated only after single-dose administration (267,317). In a study of persons with chronic liver disease (the majority with stabilized cirrhosis), no alterations in liver function were observed after a single dose. However, for persons with severe liver dysfunction, the apparent clearance of rimantadine was 50% lower than that reported for persons without liver disease (302). Rimantadine and its metabolites are excreted by the kidneys. The safety and pharmacokinetics of rimantadine among patients with renal insufficiency have been evaluated only after single-dose administration (267,305). Further studies are needed to determine multiple-dose pharmacokinetics and the most appropriate dosages for patients with renal insufficiency. In a single-dose study of patients with anuric renal failure, the apparent clearance of rimantadine was approximately 40% lower, and the elimination half-life was approximately 1.6fold greater than that among healthy persons of the same age (305). Hemodialysis did not contribute to drug clearance. In studies of persons with less severe renal disease, drug clearance was also reduced, and plasma concentrations were higher than those among control patients without renal disease who were the same weight, age, and sex (301,317). # Zanamivir In studies of healthy volunteers, approximately 7%-21% of the orally inhaled zanamivir dose reached the lungs, and 70%-87% was deposited in the oropharynx (259,318). Approximately 4%-17% of the total amount of orally inhaled zanamivir is systemically absorbed. Systemically absorbed zanamivir has a half-life of 2.5-5.1 hours and is excreted unchanged in the urine. Unabsorbed drug is excreted in the feces (259,308). # Oseltamivir Approximately 80% of orally administered oseltamivir is absorbed systemically (309). Absorbed oseltamivir is metabolized to oseltamivir carboxylate, the active neuraminidase inhibitor, primarily by hepatic esterases. Oseltamivir carboxylate has a half-life of 6-10 hours and is excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway (260,319). Unmetabolized oseltamivir also is excreted in the urine by glomerular filtration and tubular secretion (320). # Side Effects and Adverse Reactions When considering use of influenza antiviral medications (i.e., choice of antiviral drug, dosage, and duration of therapy), clinicians must consider the patient's age, weight, and renal function (Table 7); presence of other medical conditions; indications for use (i.e., prophylaxis or therapy); and the potential for interaction with other medications. # Amantadine and Rimantadine Both amantadine and rimantadine can cause CNS and gastrointestinal side effects when administered to young, healthy adults at equivalent dosages of 200 mg/day. However, incidence of CNS side effects (e.g., nervousness, anxiety, insomnia, difficulty concentrating, and lightheadedness) is higher among persons taking amantadine than among those taking rimantadine (320). In a 6-week study of prophylaxis among healthy adults, approximately 6% of participants taking rimantadine at a dosage of 200 mg/day experienced one or more CNS symptoms, compared with approximately 13% of those taking the same dosage of amantadine and 4% of those taking placebo (320). A study of older persons also demonstrated fewer CNS side effects associated with rimantadine compared with amantadine (302). Gastrointestinal side effects (e.g., nausea and anorexia) occur among approximately 1%-3% of persons taking either drug, compared with 1% of persons receiving the placebo (320). Side effects associated with amantadine and rimantadine are usually mild and cease soon after discontinuing the drug. Side effects can diminish or disappear after the first week, despite continued drug ingestion. However, serious side effects have been observed (e.g., marked behavioral changes, delirium, hallucinations, agitation, and seizures) (303,311). These more severe side effects have been associated with high plasma drug concentrations and have been observed most often among persons who have renal insufficiency, seizure disorders, or certain psychiatric disorders and among older persons who have been taking amantadine as prophylaxis at a dosage of 200 mg/day (274). Clinical observations and studies have indicated that lowering the dosage of amantadine among these persons reduces the incidence and severity of such side effects (Table 7). In acute overdosage of amantadine, CNS, renal, respiratory, and cardiac toxicity, including arrhythmias, have been reported (303). Because rimantadine has been marketed for a shorter period than amantadine, its safety among certain patient populations (e.g., chronically ill and older persons) has been evaluated less frequently. Because amantadine has anticholinergic effects and might cause mydriasis, it should not be used among patients with untreated angle closure glaucoma (303). # Zanamivir In a study of zanamivir treatment of ILI among persons with asthma or chronic obstructive pulmonary disease where study medication was administered after use of a B2-agonist, 13% of patients receiving zanamivir and 14% of patients who received placebo (inhaled powdered lactose vehicle) experienced a >20% decline in forced expiratory volume in 1 second (FEV1) after treatment (259,261). However, in a phase-I study of persons with mild or moderate asthma who did not have ILI, one of 13 patients experienced bronchospasm after administration of zanamivir (259). In addition, during postmarketing surveillance, cases of respiratory function deterioration after inhalation of zanamivir have been reported. Certain patients had underlying airway disease (e.g., asthma or chronic obstructive pulmonary disease). Because of the risk for serious adverse events and because the efficacy has not been demonstrated among this population, zanamivir is not recommended for treatment for patients with underlying airway disease (259). If physicians decide to prescribe zanamivir to patients with underlying chronic respiratory disease after carefully considering potential risks and benefits, the drug should be used with caution under conditions of appropriate monitoring and supportive care, including the availability of short-acting bronchodilators (292). Patients with asthma or chronic obstructive pulmonary disease who use zanamivir are advised to 1) have a fast-acting inhaled bronchodilator available when inhaling zanamivir and 2) stop using zanamivir and contact their physician if they experience difficulty breathing (259). No definitive evidence is available regarding the safety or efficacy of zanamivir for persons with underlying respiratory or cardiac disease or for persons with complications of acute influenza (292). Allergic reactions, including oropharyngeal or facial edema, have also been reported during postmarketing surveillance (259,269). In clinical treatment studies of persons with uncomplicated influenza, the frequencies of adverse events were similar for persons receiving inhaled zanamivir and for those receiving placebo (i.e., inhaled lactose vehicle alone) (249)(250)(251)(252)(253)(254)269). The most common adverse events reported by both groups were diarrhea; nausea; sinusitis; nasal signs and symptoms; bronchitis; cough; headache; dizziness; and ear, nose, and throat infections. Each of these symptoms was reported by <5% of persons in the clinical treatment studies combined (259). # Oseltamivir Nausea and vomiting were reported more frequently among adults receiving oseltamivir for treatment (nausea without vomiting, approximately 10%; vomiting, approximately 9%) than among persons receiving placebo (nausea without vomiting, approximately 6%; vomiting, approximately 3%) (255,256,260,321). Among children treated with oseltamivir, 14.3% had vomiting, compared with 8.5% of placebo recipients. Overall, 1% discontinued the drug secondary to this side effect (258), whereas a limited number of adults who were enrolled in clinical treatment trials of oseltamivir discontinued treatment because of these symptoms (260). Similar types and rates of adverse events were reported in studies of oseltamivir prophylaxis (260). Nausea and vomiting might be less severe if oseltamivir is taken with food (260,321). # Use During Pregnancy No clinical studies have been conducted regarding the safety or efficacy of amantadine, rimantadine, zanamivir, or oseltamivir for pregnant women; only two cases of amantadine use for severe influenza illness during the third trimester have been reported (144,145). However, both amantadine and rimantadine have been demonstrated in animal studies to be teratogenic and embryotoxic when administered at substantially high doses (301,303). Because of the unknown effects of influenza antiviral drugs on pregnant women and their fetuses, these four drugs should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus (see manufacturers' package inserts) (259,260,301,303). # Drug Interactions Careful observation is advised when amantadine is administered concurrently with drugs that affect CNS, including CNS stimulants. Concomitant administration of antihistamines or anticholinergic drugs can increase the incidence of adverse CNS reactions (248). No clinically substantial interactions between rimantadine and other drugs have been identified. Clinical data are limited regarding drug interactions with zanamivir. However, no known drug interactions have been reported, and no clinically critical drug interactions have been predicted on the basis of in vitro data and data from studies using rats (259,322). Limited clinical data are available regarding drug interactions with oseltamivir. Because oseltamivir and oseltamivir carboxylate are excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway, a potential exists for interaction with other agents excreted by this pathway. For example, coadministration of oseltamivir and probenecid resulted in reduced clearance of oseltamivir carboxylate by approximately 50% and a corresponding approximate twofold increase in the plasma levels of oseltamivir carboxylate (260,319). No published data are available concerning the safety or efficacy of using combinations of any of these four influenza antiviral drugs. For more detailed information concerning potential drug interactions for any of these influenza antiviral drugs, package inserts should be consulted. # Antiviral Drug-Resistant Strains of Influenza Amantadine-resistant viruses are cross-resistant to rimantadine and vice versa (323). Drug-resistant viruses can appear in approximately one third of patients when either amantadine or rimantadine is used for therapy (273,323,324). During the course of amantadine or rimantadine therapy, resistant influenza strains can replace susceptible strains within 2-3 days of starting therapy (325,326). Resistant viruses have been isolated from persons who live at home or in an institution where other residents are taking or have recently taken amantadine or rimantadine as therapy (327,328); however, the frequency with which resistant viruses are transmitted and their effect on efforts to control influenza are unknown. Amantadine-and rimantadine-resistant viruses are not more virulent or transmissible than susceptible viruses (329). The screening of epidemic strains of influenza A has rarely detected amantadine-and rimantadine-resistant viruses (325,330,331). Persons who have influenza A infection and who are treated with either amantadine or rimantadine can shed susceptible viruses early in the course of treatment and later shed drugresistant viruses, including after 5-7 days of therapy (273). Such persons can benefit from therapy even when resistant viruses emerge. Resistance to zanamivir and oseltamivir can be induced in influenza A and B viruses in vitro (332)(333)(334)(335)(336)(337)(338)(339), but induction of resistance usually requires multiple passages in cell culture. By contrast, resistance to amantadine and rimantadine in vitro can be induced with fewer passages in cell culture (340,341). Development of viral resistance to zanamivir and oseltamivir during treatment has been identified but does not appear to be frequent (260,(342)(343)(344)(345). In one pediatric study, 5.5% of patients treated with oseltamivir had posttreatment isolates that were resistant to neuraminidase inhibitors. One limited study of Japanese children treated with oseltamivir reported a high frequency of resistant viruses (346). However, no transmission of neuraminidase inhibitor resistant viruses in humans has been documented to date. No isolates with reduced susceptibility to zanamivir have been reported from clinical trials, although the number of posttreatment isolates tested is limited (347), and the risk for emergence of zanamivirresistant isolates cannot be quantified (259). Only one clinical isolate with reduced susceptibility to zanamivir, obtained from an immunocompromised child on prolonged therapy, has been reported (343). Available diagnostic tests are not optimal for detecting clinical resistance to the neuraminidase inhibitor antiviral drugs, and additional tests are being developed (347,348). Postmarketing surveillance for neuraminidase inhibitor-resistant influenza viruses is being conducted (349). # Sources of Information Regarding Influenza and Its Surveillance Information regarding influenza surveillance, prevention, detection, and control is available at / weekly/fluactivity.htm. Surveillance information is available through the CDC Voice Information System (influenza update) at 888-232-3228 or CDC Fax Information Service at 888-232-3299. During October-May, surveillance information is updated at least every other week. In addition, periodic updates regarding influenza are published in the MMWR Weekly Report (). Additional information regarding influenza vaccine can be obtained by calling 800-CDC-INFO (800-232-4636). State and local health departments should be consulted concerning availability of influenza vaccine, access to vaccination programs, information related to state or local influenza activity, and for reporting influenza outbreaks and receiving advice concerning outbreak control. # Additional Information Regarding Influenza Infection Control Among Specific Populations Each year, ACIP provides general, annually updated information regarding control and prevention of influenza. Other reports related to controlling and preventing influenza among specific populations (e.g., immunocompromised persons, health-care workers, hospitals, and travelers) are also available in the following publications: - CDC.

Purell Purell is an instant hand sanitizer which claims to kill "99.99% of most common germs that may cause illness in as little as 15 seconds." Its active ingredient is ethyl alcohol (62%). It is used by wetting one's hands thoroughly with the product, then briskly rubbing one's hands together until dry. Purell is the most popular hand sanitizer in the U.S. Pfizer acquired the exclusive rights to distribute Purell in the consumer market from GOJO Industries in 2004, and on June 27 2006 Johnson & Johnson announced its acquisition of the Pfizer Consumer Healthcare division, which includes the Purell brand, for $16.6 billion. In 2006, The New York Times reported that Purell is heavily used by politicians during election season, when they have to shake countless hands and remain in robust health. The product is flammable and may discolor fabrics. The inactive ingredients include water, isopropyl alcohol, glycerin, carbomer, fragrance, aminomethyl propanol, propylene glycol, isopropyl myristate, and tocopheryl acetate. # Health Risks The product is labelled as needing to be kept out of the reach of Children. The Chicago Tribune reported that children have become inebriated by ingesting Purell. One child's ingestion of the hand sanitizer caused her blood alcohol level to reach 0.218.

Sandbox:Mazia # Overview History Patients with Pancoast syndrome may present with referred pain over the scapula to the shoulder as the result of damage to the afferent pain fibers of the sympathetic trunk. The symptoms are typical of the location of the tumor in the superior sulcus or thoracic inlet adjacent to the eighth cervical nerve roots, the first and second thoracic trunk distribution, the sympathetic chain, and the stellate ganglion. Initially, localized pain occurs in the shoulder and vertebral border of the scapula. Pain may later extend along an ulnar nerve distribution of the arm to the elbow and, ultimately, to the ulnar surface of the forearm and to the small and ring fingers of the hand (C8). If the tumor extends to the sympathetic chain and stellate ganglion, Horner syndrome and anhidrosis develop on the ipsilateral side of the face and upper extremity. The pain is frequently relentless and unremitting, and adequate relief often requires administration of narcotics. The patient usually supports the elbow of the affected arm in the hand of the opposite upper extremity to ease the tension on the shoulder and upper arm. The hand muscles may become weak and atrophic, and the triceps reflex may be absent. The first or second rib or vertebrae may be involved by tumor extension and intensify the severity of pain. The spinal canal and spinal cord may be invaded or compressed, with subsequent symptoms of spinal cord tumor or cervical disk disease. Many patients are initially treated for presumed local musculoskeletal conditions such as bursitis and vertebral osteoarthritis with radicular pain. Symptoms may persist for many months before evaluation for progression reveals the cause. In a 1994 series by Maggi et al, symptoms lasted 2-36 months, with a mean of 9.7 months. In 1997, Muscolino described plexopathy or radicular symptoms in 53% of 15 patients. # Historical Perspective - was first discovered by , a , in during/following . - In , mutations were first identified in the pathogenesis of . - In , the first was developed by to treat/diagnose . # Classification - may be classified according to into subtypes/groups: - Other variants of include , , and . # Pathophysiology - The pathogenesis of is characterized by , , and . - The gene/Mutation in has been associated with the development of , involving the pathway. - On gross pathology, , , and are characteristic findings of . - On microscopic histopathological analysis, , , and are characteristic findings of . # Causes - may be caused by either , , or . - is caused by a mutation in the , , or gene. - There are no established causes for . # Differentiating from other Diseases - must be differentiated from other diseases that cause , , and , such as: # Epidemiology and Demographics - The prevalence of is approximately per 100,000 individuals worldwide. - In , the incidence of was estimated to be cases per 100,000 individuals in . ## Age - Patients of all age groups may develop . - is more commonly observed among patients aged years old. - is more commonly observed among . ## Gender - affects men and women equally. - are more commonly affected with than . - The to ratio is approximately to 1. ## Race - There is no racial predilection for . - usually affects individuals of the race. - individuals are less likely to develop . # Risk Factors - Common risk factors in the development of are , , , and . # Natural History, Complications and Prognosis - The majority of patients with remain asymptomatic for . - Early clinical features include , , and . - If left untreated, of patients with may progress to develop , , and . - Common complications of include , , and . - Prognosis is generally , and the of patients with is approximately . # Diagnosis ## Diagnostic Criteria - The diagnosis of is made when at least of the following diagnostic criteria are met: ## Symptoms - is usually asymptomatic. - Symptoms of may include the following: ## Physical Examination - Patients with usually appear . - Physical examination may be remarkable for: ## Laboratory Findings - There are no specific laboratory findings associated with . - A is diagnostic of . - An concentration of is diagnostic of . - Other laboratory findings consistent with the diagnosis of include , , and . ## Imaging Findings - There are no findings associated with . - is the imaging modality of choice for . - On , is characterized by , , and . - may demonstrate , , and . ## Other Diagnostic Studies - may also be diagnosed using . - Findings on include , , and . # Treatment ## Medical Therapy - There is no treatment for ; the mainstay of therapy is supportive care. - The mainstay of therapy for is and . - acts by . - Response to can be monitored with every . ## Surgery - Surgery is the mainstay of therapy for . - in conjunction with is the most common approach to the treatment of . - can only be performed for patients with . ## Prevention - There are no primary preventive measures available for . - Effective measures for the primary prevention of include , , and . - Once diagnosed and successfully treated, patients with are followed-up every . Follow-up testing includes , , and .

Adult T-cell leukemia overview # Overview Adult T‐cell leukemia arises from post‐thymic lymphocytes, which are normally involved in the process of cell-mediated immune response. Development of adult T-cell leukemia is the result of multiple genetic mutations, induced by an infection with human T‐cell lymphotropic virus (HTLV). On gross pathology, skin nodules, maculopapular eruption, and erythema are characteristic skin findings of adult T-cell leukemia. On microscopic histopathological analysis, characteristic findings of adult T-cell leukemia include pleomorphic, medium sized lymphocytes with a polylobulated nucleus and agranular cytoplasm. Based on both the clinical presentation and lab values, adult T-cell leukemia may be classified into either an acute variant, chronic variant, smoldering variant, or an adult T-cell lymphoma variant. The majority of adult T-cell leukemia cases are reported in Japan, the Caribbean, South America, and Africa. The natural history of adult T-cell leukemia varies between the different sub-types of the disease. Common complications of adult T-cell leukemia include cardiac arrhythmias, opportunistic infections, and bone fractures. The prognosis varies between the sub-types of adult T-cell leukemia. Acute and lymphomatous sub-types have a poor prognosis; whereas chronic and smoldering sub-types have a good prognosis. The optimal therapy for adult T-cell leukemia depends on the clinical variant of the disease. Chronic and smoldering adult T-cell leukemia patients are usually managed by either observation, skin directed therapies, or a combination of zidovudine and interferon therapy. Acute adult T-cell leukemia patients are usually managed by either chemotherapy, supportive care, allogeneic stem cell transplant, or a combination of zidovudine and interferon therapy. The first line chemotherapeutic regimens used for the initial management of adult T-cell leukemia include CHOP, CHOEP, or Dose-adjusted EPOCH. Second line chemotherapeutic agents might be DHAP, ESHAP, GDP, GemOx, or ICE. Surgery is not the first-line treatment option for patients with adult T-cell leukemia. Splenectomy is usually reserved for certain cases of adult T-cell leukemia. No preventive vaccine against HTLV-1 is currently available. # Historical Perspective Adult T-cell leukemia was first discovered in 1977 by Dr. K. Takatsuki, a Japanese physician. The association between HTLV infection and adult T-cell leukemia was made in 1981. # Classification Based on both the clinical presentation and laboratory findings, adult T-cell leukemia may be classified into either an acute variant, chronic variant, smoldering variant, or an adult T-cell lymphoma variant. # Pathophysiology Adult T‐cell leukemia arises from post‐thymic lymphocytes, which are normally involved in the process of cell-mediated immune response. Development of adult T-cell leukemia is the result of multiple genetic mutations induced by an infection with human T‐cell lymphotropic virus (HTLV). On gross pathology, skin nodules, maculopapular eruption, and erythema are characteristic skin findings of adult T-cell leukemia. On microscopic histopathological analysis, characteristic findings of adult T-cell leukemia include pleomorphic, medium sized lymphocytes with a polylobulated nucleus and agranular cytoplasm. # Causes Adult T-cell leukemia is caused by an infection with HTLV. Common genetic mutations involved in the development of adult T-cell leukemia can be found here. # Differentiating Adult T-cell leukemia from other Diseases Adult T-cell leukemia must be differentiated from other diseases that cause weight loss, night sweats, hepatosplenomegaly, and palpable lymph nodes, such as hairy cell leukemia, prolymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma. # Epidemiology and Demographics The majority of adult T-cell leukemia cases are reported in Japan, the Caribbean, South America, and Africa. In southern Japan, the age-adjusted incidence rate of adult T-cell leukemia is approximately 6.6 per 100,000 individuals. The incidence of adult T-cell leukemia increases with age, and the median age at diagnosis is 57 years. Males are more commonly affected with adult T-cell leukemia than females. The male to female ratio is approximately 1.4 to 1. Adult T-cell leukemia usually affects individuals of the African American, Latin American, and Asian race. Caucasian individuals are less likely to develop adult T-cell leukemia. # Risk Factors Common risk factors in the development of adult T-cell leukemia among HTLV carriers are vertical transmission of HTLV infection during labor, male sex, and specific human leukocyte antigens such as HLA-A 26, HLA-B 4002, and HLA-B 4801. # Screening According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for adult T-cell leukemia. # Natural History, Complications and Prognosis The natural history of adult T-cell leukemia varies between the different sub-types of the disease. Common complications of adult T-cell leukemia include cardiac arrhythmias, opportunistic infections , and bone fractures. The prognosis varies between the sub-types of adult T-cell leukemia. Acute and lymphomatous sub-types have a poor prognosis; whereas chronic and smouldering sub-types have a good prognosis. # Diagnosis ## Diagnostic Study of Choice There is no single diagnostic study of choice for the diagnosis of adult T-cell leukemia. However, adult T-cell leukemia can be diagnosed based on clinical manifestation and laboratory findings confirming characteristic histopathology and HTLV-1 infection. ## History and Symptoms Symptoms of adult T-cell leukemia include fatigue, fever, night sweats, constipation, and recurrent infections. ## Physical Examination Patients with adult T-cell leukemia usually appear lethargic and fatigued. Physical examination of patients with adult T-cell leukemia is usually remarkable for maculopapular rash, skin ulceration, and splenomegaly. ## Laboratory Findings Laboratory findings consistent with the diagnosis of adult T-cell leukemia include abnormal anemia, thrombocytopenia, and elevated lymphocyte count. Hypercalcemia is a key feature among patients with adult T-cell leukemia. ## Electrocardiogram There are no ECG findings associated with adult T-cell leukemia. However, electrocardiogram might be helpful in detecting complications of adult T-cell leukemia such as cardiac arrhythmias due to hypercalcemia. To view the electrocardiogram findings in hypercalcemia, click here. ## X-ray There are no x-ray findings associated with adult T-cell leukemia. However, an x-ray may be helpful in the diagnosis of complications of adult T-cell leukemia, which include bone fractures and lytic lesions. ## Echocardiography and Ultrasound There are no echocardiography findings associated with adult T-cell leukemia. Findings on an ultrasound suggestive of adult T-cell leukemia include hepatomegaly, splenomegaly and lymphadenopathy. ## CT Scan Thoracic CT scan may be helpful in the diagnosis of adult T-cell leukemia. Findings on CT scan suggestive of pulmonary infiltration by adult T-cell leukemia cells include thickening of the bronchovascular bundles, consolidation in the peripheral lung parenchyma, and ground-glass attenuations. Findings on abdominal CT scan suggestive of adult T-cell leukemia cells include hepatomegaly and splenomegaly. ## MRI There are no MRI findings associated with adult T-cell leukemia. ## Other Imaging Findings There are no other imaging findings associated with adult T-cell leukemia. ## Other Diagnostic Studies Other diagnostic studies for adult T-cell leukemia include skin biopsy, bone marrow biopsy, and fluorescent in-situ hybridization. # Treatment ## Medical Therapy The optimal therapy for adult T-cell leukemia depends on the clinical variant of the disease. Chronic and smoldering adult T-cell leukemia patients are usually managed by either observation, skin directed therapies, or a combination of zidovudine and interferon therapy. Acute adult T-cell leukemia patients are usually managed by either chemotherapy, supportive care, allogeneic stem cell transplant, or a combination of zidovudine and interferon therapy. The first line chemotherapeutic regimens used for the initial management of adult T-cell leukemia include CHOP, CHOEP, or Dose-adjusted EPOCH. Second line chemotherapeutic agents might be DHAP, ESHAP, GDP, GemOx, or ICE. ## Interventions The mainstay of treatment for Adult T-cell leukemia is medical therapy. There are no recommended therapeutic interventions for the management of Adult T-cell leukemia. ## Surgery Surgery is not the first-line treatment option for patients with adult T-cell leukemia. Splenectomy is usually reserved for certain cases of adult T-cell leukemia. ## Primary Prevention Primary prevention of adult-T cell leukemia is aimed at preventing the vertical and person-person transmission of HTLV virus. No preventive vaccine against HTLV-1 is currently available. ## Secondary Prevention There are no established measures for the secondary prevention of Adult T-cell leukemia.

Phloroglucinol # Overview Phloroglucinol is an organic compound that is used in the synthesis of pharmaceuticals and explosives. It is a phenol derivative with antispasmodic properties that is used primarily as a laboratory reagent. Austrian chemist Heinrich Hlasiwetz (1825-1875) is remembered for his chemical analysis of phloroglucinol. Phloroglucinol is also generally found in the flavonoid ring A substitution pattern. # Chemistry Phloroglucinol (1,3,5-benzenetriol) is a benzenetriol, found along with two isomers, hydroxyquinol (1,2,4-benzenetriol) and pyrogallol (1,2,3-benzenetriol). Phloroglucinol, and its benzenetriol isomers, are still defined as “phenols” according to the IUPAC official nomenclature rules of chemical compounds. Many such monophenolics are often quoted as “polyphenols” by the cosmetic and parapharmaceutic industries, but they cannot be by any scientifically-accepted definition. This molecule has a unique symmetric arene substitution pattern of a trisubstituted benzene. It is a type of enol. exists in two forms, or tautomers, 1,3,5-trihydroxybenzene, which has phenol-like, and 1,3,5-cyclohexanetrione (phloroglucin), which has ketone-like character. These two tautomers are in equilibrium. Phloroglucinol is a useful intermediate because it is polyfunctional. Furthermore, the deprotonated intermediate in the interconversion of the two forms, referred to as an enolate anion, is important in carbonyl chemistry, in large part because it is a strong nucleophile. From water, phloroglucinol crystallizes as the dihydrate, which has a melting point of 116–117 °C, but the anhydrous form melts at a much higher temperature, at 218–220 °C. It does not boil intact, but it does sublime. ## Isolation Phloroglucinol was originally isolated from phloretin, a compound found in fruit trees, using potassium hydroxide. Additionally, the compound can be similarly prepared from glucosides, plant extracts and resins such as quercetin, catechin and phlobaphenes. ## Synthesis It is synthesized via a number of processes, but representative is the following route from trinitrobenzene. It is a selective trinitration where benzene is symmetrically trinitrated to 1,3,5 trinitrobenzene to produce a precursor for the synthesis of phloroglucinol. The synthesis is noteworthy because ordinary aniline derivatives are unreactive toward hydroxide. Because the triaminobenzene also exists as its imine tautomer, it is susceptible to hydrolysis. ## Reactions The compound behaves like a ketone in its reaction with hydroxylamine, forming the tris(oxime). But it behaves also like a benzenetriol (Ka1 = 3.56 × 10−9, Ka2 1.32×10−9), as the three hydroxyl groups can be methylated to give 1,3,5-trimethoxybenzene. The Hoesch reaction allows the synthesis of 1-(2,4, 6-Trihydroxyphenyl)ethanone from phloroglucinol. Leptospermone can be synthesized from phloroglucinol by a reaction with isovaleroylnitrile in the presence of a zinc chloride catalyst. Pentacarbon dioxide, described in 1988 by Günter Maier and others, can be obtained by pyrolysis of 1,3,5-cyclohexanetrione (phloroglucin). # Natural occurrences Phloroglucinols are secondary metabolites that occur naturally in certain plant species. It is also produced by organisms that are not plants such as brown algae or bacteria. Acyl dervatives are present in the fronds of the coastal woodfern, Dryopteris arguta or in Dryopteris crassirhizoma. The anthelmintic activity of the root of Dryopteris filix-mas has been claimed to be due to flavaspidic acid, a phloroglucinol derivative. Formylated phloroglucinol compounds (euglobals, macrocarpals and sideroxylonals) can be found in Eucalyptus species. Hyperforin and adhyperforin are two phloroglucinols found in St John's wort. Humulone is a phloroglucinol derivative with three isoprenoid side-chains. Two side-chains are prenyl groups and one is an isovaleryl group. Humulone is a bitter-tasting chemical compound found in the resin of mature hops (Humulus lupulus). Brown algae, such as Ecklonia stolonifera, Eisenia bicyclis or species in the genus Zonaria, produce phloroglucinol and phloroglucinol derivatives. Brown algae also produce a type of tannins known as phlorotannins. The bacterium Pseudomonas fluorescens produces phloroglucinol, phloroglucinol carboxylic acid and diacetylphloroglucinol. # Biosynthesis In Pseudomonas fluorescens, biosynthesis of phloroglucinol is performed with a type III polyketide synthase. The synthesis begins with the condensation of three malonyl-CoAs. Then decarboxylation followed by the cyclization of the activated 3,5-diketoheptanedioate product leads to the formation of phloroglucinol. The enzyme pyrogallol hydroxytransferase uses 1,2,3,5-tetrahydroxybenzene and 1,2,3-trihydroxybenzene (pyrogallol) to produce 1,3,5-trihydroxybenzene (phloroglucinol) and 1,2,3,5-tetrahydroxybenzene. It is found in the bacterium species Pelobacter acidigallici. The enzyme phloroglucinol reductase uses dihydrophloroglucinol and NADP+ to produce phloroglucinol, NADPH, and H+. It is found in the bacterium species Eubacterium oxidoreducens. The legume-root nodulating, microsymbiotic nitrogen-fixing bacterium species Bradyrhizobium japonicum is able to degrade catechin with formation of phloroglucinol carboxylic acid, further decarboxylated to phloroglucinol, which is dehydroxylated to resorcinol and hydroxyquinol. Phloretin hydrolase uses phloretin and water to produce phloretate and phloroglucinol. # Potential health effects It is also used as a treatment for gallstones, spasmodic pain and other related gastrointestinal disorders. It has a non-specific spasmolytic action on the vessels, bronchi, intestine, ureters and gall bladder, and is used for treating disorders of these organs. It is the main ingredient of the drug Spasfon, commercialized in France, where it is one of the most sold drugs. Phloroglucinols acylated derivatives have a fatty acid synthase inhibitory activity. ## Codes in medical literature It has the A03AX12 code in the A03AX Other drugs for functional bowel disorders section of the ATC code A03 Drugs for functional gastrointestinal disorders subgroup of the Anatomical Therapeutic Chemical Classification System. It also has the D02.755.684 code in the D02 Organic chemicals section of the Medical Subject Headings (MeSH) codes by the United States National Library of Medicine. # Applications Phloroglucinol is mainly used as a coupling agent in printing. It links diazo dyes to give a fast black. It is useful for the industrial synthesis of pharmaceuticals (Flopropione) and explosives (TATB (2,4,6-triamino-1,3,5- trinitrobenzene), trinitrophloroglucinol, 1,3,5-trinitrobenzene). Phloroglucinolysis is an analytical technique to study condensed tannins by means of depolymerisation. The reaction makes use of phloroglucinol as nucleophile. Phlobaphenes formation (tannins condensation and precipitation) can be minimized in using strong nucleophiles, such as phloroglucinol, during pine tannins extraction. ## Use in tests Phloroglucinol is a reagent of the Tollens’ test for pentoses. This test relies on reaction of the furfural with phloroglucinol to produce a colored compound with high molar absorptivity. A solution of hydrochloric acid and phloroglucinol is also used for the detection of lignin (Wiesner test). A brilliant red color develops, owing to the presence of coniferaldehyde groups in the lignin. A similar test can be performed with tolonium chloride. It is also part of Gunzburg reagent, an alcoholic solution of phloroglucinol and vanillin, for the qualitative detection of free hydrochloric acid in gastric juice.

Balloon catheter insertion for Bartholin's cyst or abscess # Guidance Current evidence on the safety and efficacy of balloon catheter insertion for Bartholin's cyst or abscess is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.# The procedure # Indications and current treatments Bartholin's glands are located at the vaginal entrance. During sexual arousal, they secrete a lubricant which enters the vagina through a small duct from each gland. A cyst may form if the duct becomes obstructed, and if the cyst becomes infected then an abscess develops. Conservative management of symptomatic cysts or abscesses may include warm baths, compresses, analgesics, and antibiotics when appropriate. Persistent and symptomatic cysts or abscesses are often treated surgically, by incision and drainage, or by marsupialisation (where the cyst is opened, and the skin edges are stitched to allow continual free drainage of the fluid from the cyst cavity). # Outline of the procedure The aim of the procedure is to establish drainage of the abscess or cyst by creating a fistula or sinus track that will remain open in the long term. The underlying principle is that a foreign body reaction (to the balloon and catheter) induces formation of an epithelialised fistula. With the patient under local or general anaesthesia, an incision is made into the abscess or cyst on the mucosal surface of the labia minora. A tissue specimen (biopsy) and/or swab may be taken to test for neoplasia and/or infection (including sexually transmitted diseases). The abscess or cyst is drained. A specially designed balloon catheter is inserted into the abscess or cyst cavity through the incision, and the balloon is inflated with saline to secure it in place. If pain persists after the balloon is inflated, it is partially deflated, leaving enough fluid to keep the catheter in position. A suture may be used to partially close the incision and hold the catheter in place. The catheter stays in, usually for up to 4 weeks, to allow epithelialisation of the tract, after which it is deflated and removed. A period of a few weeks may be required for epithelialisation. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A prospective case series of 35 women with Bartholin's abscess treated by balloon catheter insertion reported operative success (defined as short-term abscess resolution with no need for marsupialisation and no recurrence) in 97% (34/35) of women. The study reported that 89% (24/27) of women who retained the catheter for 4 weeks would recommend the procedure. In the case series of 35 women, catheters were successfully inserted in 34. Of these, 7 fell out: 3 after 24 hours, 3 after 1 week and 1 after 11 days. Despite their catheters falling out, 6 of the 7 women were reported as having successful outcomes. One woman had subsequent marsupialisation. Epithelialisation was judged to have occurred in the remaining 27 women 4 weeks after treatment. A case series of 46 women with Bartholin's cyst or abscess treated by balloon catheter reported recurrence in 17% (8/46) of women, and the procedure was repeated in all patients (the paper did not state whether these repeat procedures were successful or not). Another case series (68 women with Bartholin's cyst or abscess) reported 2 cyst recurrences (without infection) 6 months and 5 years after the procedure. For the first recurrence, it was thought that the catheter was removed prematurely. The Specialist Advisers listed key efficacy outcomes as healing in the short term and absence of abscess recurrence 6 months after the procedure. # Safety The case series of 68 women reported necrotic abscess development in 1 woman because the inflated balloon eroded the cutaneous surface of the labium (time of occurrence not stated). This was considered to have been caused by improper insertion of the catheter. The same case series reported that another woman was admitted to hospital for 9 days because the catheter had been inserted between the vestibular mucosa and the cyst wall. The cyst remained 1 year after the operation. The case series of 35 women reported that 5 women complained of mild discomfort (scoring 2–3 on a pain scale from 0 to 10 ) on sitting at 1-week follow-up. One woman reported moderate discomfort (scoring 5 on the same scale) and a continuous sensation of labial swelling, which subsided when 2 ml of fluid was removed from the balloon (time of occurrence not stated). The Specialist Advisers listed an anecdotal adverse event as pain if the catheter is overfilled, which could be relieved by slightly deflating it. They considered theoretical adverse events to include infection, abscess recurrence, bleeding, pain from having the catheter in situ, scarring, expulsion of the bulb of the catheter and dyspareunia.# Further information # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk

SULF1 Sulfatase 1, also known as SULF1, is an enzyme which in humans is encoded by the SULF1 gene. Heparan sulfate proteoglycans (HSPGs) act as co-receptors for numerous heparin-binding growth factors and cytokines and are involved in cell signaling. Heparan sulfate 6-O-endo-sulfatases, such as SULF1, selectively remove 6-O-sulfate groups from heparan sulfate. This activity modulates the effects of heparan sulfate by altering binding sites for signaling molecules. # Function Heparan sulfate proteoglycans (HSPGs) are widely expressed throughout most tissues of nearly all multicellular species. The function of HSPGs extends beyond providing an extracellular matrix (ECM) structure and scaffold for cells. They are integral regulators of essential cell signaling pathways affecting cell growth, proliferation, differentiation, and migration. Although the core protein is important, the large heparan sulfate (HS) chains extending from the core are responsible for most receptor signaling. HS chains are heterogeneous structures that differ in specific and conditional cell contexts. Of particular importance is the HS sulfation pattern, which was once thought to be static after HS biosynthesis in the Golgi. However, this paradigm changed after the discovery of two extracellular 6-O-S glucosamine arylsulfatases, Sulf1 and Sulf2. These two enzymes allow rapid extracellular modification of sulfate content in HSPGs, impacting signaling involving Shh, Wnt, BMP, FGF, VEGF, HB-EGF, GDNF, and HGF. In addition, Sulfs may exercise another level of regulation over HS composition by down or upregulating HS biosynthetic enzymes present in the Golgi through the very same signaling pathways they modify. # Discovery Before the cloning and characterization of Sulf1 and Sulf2, HS composition was thought to be unchanging after localization to the cell surface. However, this changed when the quail orthologue of Sulf1, QSulf1, was identified in a screen for Sonic hedgehog (Shh) response genes activated during somite formation in quail embryos. Sequence alignment analysis indicates QSsulf1 is homologous with lysosomal N-acetyl glucosamine sulfatases (G6-sulfatases) that catalyze the hydrolysis of 6-O sulfates from N-acetyl glucosamines of heparan sulfate during the degradation of HSPGs. In contrast to lysosomal active sulfatases, QSulf1 localizes exclusively to the cell surface by interacting hydrophilically with a non-heparan sulfate outer membrane component, and is enzymatically active at a neutral pH. By mutating the catalytically active cysteines to alanine, thereby blocking N-formylglycine formation, they found QSulf1 was responsible for Wingless (Wnt) release from HS chains to activate the Frizzled receptor; this was the first evidence that an extracellular sulf was capable of modifying HS and therefore cell signaling. The overall structure of QSulf is followed closely by its orthologues and paralogues, including human and mouse. The human and murine orthologues of QSulf1, HSulf1 and MSulf1, respectively, were cloned and characterized after the discovery of QSulf1. In addition, a paralogue, Sulf2, sharing 63-65% identity (both mouse and human) with Sulf1 also was discovered through BLAST sequence analysis. The HSulf1 gene (GenBank accession number AY101175) has an open reading frame of 2616 bp, encoding a protein of 871 amino acid (aa), and HSulf2 (GenBank accession number AY101176) has an open reading frame of 2613 bp, encoding a protein of 870 aa. The HSulf1 and 2 genes localize to 8q13.2-13.3 and 20q13.12, respectively. They contain putative Asn-linked glycosylation sites, and furin cleavage sites responsible for proteolytic processing in the Golgi. The function or substrate specificity these cleavage sites impart has yet to be determined. Validation of the predicted N-linked glycosylation sites on QSulf1 were performed using tunicamycin and QSulf1 variants missing the N-terminal (catalytic) domain or HD, which contain predicted N-linked glycosylation sites. The N- and C-terminal showed unbranched N-linked glycosylation, but was absent in the hydrophilic domain even though it contains two putative sites. In addition, O-linked or sialylated glycosylation were not present in QSulf1. Importantly, proper glycosylation is necessary to localize to the cell surface, possibly to bind HS moieties, and was required for enzymatic activity. # Structure and mechanism Sulf1 and Sulf2 are new members of a superfamily of arylsulfatases, being closely related to arylsulfatase A, B (ARSA; ARSB) and glucosamine 6-sulfatase (G6S). The x-ray crystal structure of neither Sulf1 or Sulf2 has been attempted, but ARSA active site crystal structure was deciphered. In ARSA, the conserved cysteine, which is posttranslationally modified to a C alpha formylglycine (FG) is critical for catalytic activity. In the first step, one of the two oxygens of the aldehyde hydrate attacks the sulfur of the sulfate ester. This leads to a transesterification of the sulfate group onto the aldehyde hydrate. Simultaneously the substrate alcohol is released. In the second step, sulfate is eliminated from the enzyme-sulfate intermediate by an intramolecular rearrangement. The “intramolecular hydrolysis” allows the aldehyde group to be regenerated. The active site of ARSA contains nine conserved residues that were found to be critical for catalytic activity. Some residues, such as Lys123 and Lys302, bind the substrate while others either participate in catalysis directly, such as His125 and Asp281, or indirectly. In addition a magnesium ion is needed to coordinate the oxygen that attacks the sulfur in the first step of sulfate cleavage. The crystal structure and residue mutations need to be performed in Sulf1 and Sulf2 to determine if any differences exist from lysosomal sulfatases. # Enzymatic specificity HS enzymatic specificity of QSulf1 was first analyzed. QSulf1 enzymatic specificity on 6-O sulfates was linked to the trisulfated disaccharides (HexA,2SGlcNS,6S) in S domains of HS (HS regions where most of the GlcNS residues are in contiguous sequences) and not NA/NS domains (regions of alternating N-acetylated and N-sulfated units; transition zones). Sulf1 and 2 null murine embryonic fibroblasts were generated to test the HS specificity of mammalian Sulf as opposed to avian Sulf (QSulf). Investigators found mSulf1−/−;mSulf2−/− HS showed overall large increases in all 6S disaccharides. Cooperativity between mSulf1/2 was found because a 2-fold increase in S-domain-associated disaccharides (UA–GlcNS(6S) and UA(2S)–GlcNS(6S)) was observed in double knock-out HS as compared with either single knock-out HS alone. However, one difference from mSulf1 is that mSulf2−/− HS shows an increase in 6S almost exclusively within the non-sulfated and transition zones. This sulfation effect on non-sulfated and transition zones is also different from QSulfs, which catalyze desulfation exclusively in S-domains. Although 6S changes were dominant, other small changes in NS and 2S sulfation do occur in the Sulf knock out MEFs, which may be a compensatory mechanism. Further biochemical studies elucidated specificity and localization of human Sulfs 1 and 2. Sulf1 and 2 hydrophilic domains associate with the cell membrane components through electrostatic interactions and not by integration with into the lipid bilayer. In addition to cell membrane association, Sulfs also secreted freely into the media, which contrasts the findings with QSulf1 and 2. Biochemical analysis of HSPGs in Sulf 1 and 2 knockout MEFS reveal enzyme specificities to disulfated and, primarily, trisulfated 6S disaccharide units UA-GlcNS(6S) and UA(2S)-GlcNS(6S) within the HS chain, with specific exclusion of monosulfated disaccharide units. In vivo studies, however, demonstrate that loss of Sulf1 and Sulf2 result in sulfation changes of nonsubstrates (UA-GlcNAc(6S), N and 2-O Sulfate), indicating Sulf modulates HS biosynthetic machinery. This was further demonstrated by PCR analysis, showing dynamic changes in HS biosynthesis enzymes after Sulf1 and 2 loss. Also, the authors showed in an MEF model system, that Sulf1 and Sulf2 definitively and differentially modify HS proteoglycan fractions including cell surface, GPI-anchored (glypican), shed, and ECM-associated proteoglycans. # Role in cancer The next section gives a detailed description of Sulf1 and Sulf2’s involvement in cancer. Much of what is known about signaling pathways mediated by Sulfs has been determined through investigating extracellular Sulf role and function in cancer. Therefore, they will be described in tandem. Additionally, this emphasizes how small changes in HS sulfation patterns have major impacts in health and disease. ## Ovarian Cancer The first signs of Sulf1 dysregulation were found in ovarian cancer. The expression of Sulf1 mRNA was found to be downregulated or absent in a majority of ovarian cancer specimens. The same investigators also found lowered mRNA expression in breast, pancreatic, and hepatic malignant cell lines. This absent or hypomorhic Sulf1 expression results in highly sulfated HSPGs. The lack of Sulf1 expression also augments heparin binding-epidermal growth factor (HB-EGF) response by way of greater EGF Receptor (EGFR) and extracellular signal-regulated kinase (ERK) signaling, which are common signatures of ovarian cancer. Even further, Sulf1 N-terminal sulfatase actitivity was specifically required for cisplatin-induced apoptosis of the ovarian cancer cell line, OV207. The mechanism by which Sulf1 is downregulated in ovarian cancer was investigated. Epigenetic silencing of CpG sites within Sulf1 exon 1A by methylation is associated with ovarian cancer cells and primary ovarian cancer tissues lacking Sulf1 expression. Furthermore, CpG sites showed increased levels of histone H3 K9 methylation in Sulf1 negative ovarian cancer cell lines. ## Breast Cancer Breast cancer expression of Sulf1 at the mRNA level was shown to be downregulated. Investigations into this relationship revealed that angiogenesis in breast cancer was shown to be regulated in part by Sulf1. Breast cancer xenografts overexpressing Sulf1 in athymic mice showed marked decreases in angiogenesis. Specifically, Sulf1 inhibited the ability of vascular endothelial cell heparan sulfate to participate in complex formation with FGF-2, thereby abolishing growth signaling. FGF-2 is a HB-GF, requiring the formation of a ternary complex with HS and the FGF Receptor (FGFR) to cause receptor dimerization, activation, and autophosphorylation, which then leads to induction of the mitogen-activated protein kinase (MAPK) pathway (in addition to other pathways). This results in several responses including cell proliferation and angiogenesis. Importantly, this response is dependent upon the degree and signature of HS-GAG sulfation. To further validate the response in breast cancer, human umbilical vein endothelial cells (HUVECs), overexpressing Sulf1 inhibited vascular endothelial growth factor 165 (VEGF165) signaling which is dependent upon HS, but not HS-independent VEGF121. Sulf2 also was implicated in breast cancer. In contrast to Sulf1, Sulf2 was upregulated at both the mRNA and protein levels in tumor tissue in two mammary carcinoma mouse models. Sulf1 displays regulation of amphiregulin and HB-EGF-mediated autocrine and paracrine signaling in breast cancer. Loss of Sulf1 in a breast cancer cell line, MDA-MB-468, shows increased ERK1/2 and EGFR activation, which was shown to be mediated by HB-EGF and amphiregulin, which require complexes with specifically sulfated HS. Breast cancer samples show loss of Sulf1 expression in invasive lobular carcinomas. These carcinomas are predominantly, estrogen receptor (ER) and progesterone receptor (PR)-positive, and HER-2, p53, and EGFR-negative (markers indicating increased aggressiveness of breast cancer), but do not confer an increased survival. The authors suggest that enhanced amphiregulin and HB-EGF signaling due to a lack of Sulf1, and therefore oversulfation of HS, may make lobular carcinomas more aggressive than expected. The mechanism by which Sulf1 is downregulated in breast cancer (and gastric cancer) was further investigated. The authors found aberrant hypermethylation of the Sulf1 promoter in both breast cancer and gastric cancer cell lines and patient samples, leading to a reduction of Sulf1 expression, which is similar to ovarian cancer. Despite this evidence, disagreements are found in the literature regarding the role of Sulf in breast cancer. In contrast to previous reports, Sulf1 transcript expression was highly upregulated in invasive ductal carcinoma with respect to confined ductal carcinoma in situ. The authors, therefore, propose that Sulf1 is involved in the acquisition of the capacity to invade adjacent tissues in ductal carcinoma in situ. ## Hepatocellular Carcinoma Cancer cell lines with downregulation of Sulf1 were investigated in the same fashion as ovarian cancer. Nine of 11 hepatocellular carcinoma (HCC) cell lines displayed either absent or severely reduced levels of Sulf1 mRNA. Less than half of HCC tumor samples showed loss of heterozygosity (LOH), and DNA methylation inhibition treatment of Sulf1 absent HCC cell lines reactivated the expression of Sulf1, indicating hypermethylation may be partly responsible for its downregulation. As in ovarian cancer, loss of Sulf1 largely contributed to decreased HPSG sulfation in HCC. In addition, Sulf1 expression is required to suppress sustained activation of ERK1/2 and c-met by the heparin binding growth factors (HB-GF), fibroblast growth factor (FGF) and hepatocyte growth factor (HGF), thereby decreasing cell proliferation. In extension, Sulf1 mediated HCC cell apoptotic sensitivity to cisplatin and staurosporine. As a review, HGF, or scatter factor, activates its receptor c-Met which activates mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) and PI3K signaling that are ultimately responsible for expression of proangiogenic factors, interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF). The HGF/c-Met axis mediates the invasive growth phenotype necessary for metastasis through coordination of cell motility and degradation of extracellular matrix (ECM). In vivo studies on HCC found Sulf1 overexpressing HCC xenografts displayed delayed tumor growth in mice, and the mechanism involves inhibition of histone deacetylase (HDAC). Sulf1 enhances acetylation of Histone H4 by inhibiting HDAC, which subsequently inhibits the activation of the MAPK and Akt pathways ultimately decreasing HCC tumorogenesis. Sulf2’s role in HCC contrasted with Sulf1. Sulf2 was upregulated in a majority of HCCs and HCC cell lines, and Sulf2 knockdown eliminated migration and proliferation. Sulf2 also upregulated glypican-3, which is commonly overexpressed in HCC, by increasing ERK, AKT activation through enhanced FGF2 signaling. GPC3 is important in Sulf2-enhanced FGF signaling in vitro, so glypican-3 may mediate its own upregulation through Sulf2. Given that Sulf1 and Sulf2 have redundant functions, Sulf2 contrasting function in HCC was unexpected. ## Pancreatic Cancer Sulf1 mRNA expression in pancreatic cancer differed from ovarian and liver cancer. Only 50% of pancreatic cancer cell lines tested exhibited a significant decrease in Sulf1. Further, in situ hybridization demonstrated that Sulf1 mRNA expression was not uniformly absent in pancreatic cancer tissue. In fact, Sulf1 was present weakly in normal acinar cells, but present at high levels in the endothelium and malignant cells in pancreatic cancer tissue (Li, Kleeff et al. 2005). This indicates that downregulation of Sulf1 is not a ubiquitous process in carcinogenesis. Nevertheless, endogenous expression of Sulf1 in a Sulf1-negative pancreatic cancer cell line, PANC-1, inhibited FGF-2 signaling, but did not affect HB-EGF, EGF, or insulin-like growth factor-1 (IGF-1) signaling, indicating cell specific effects. In further contrast to ovarian cancer and HCC, Hsulf-1 expressing Panc-1 cells were more resistant to gemcitabine, suggesting Hsulf-1 over-expression might confer increased chemoresistance, and therefore a growth advantage, to pancreatic cancer cells. In further reports Sulf1 displays a complicated expression pattern in pancreatic cancer that is more than merely up or downregulation. For instance, primary pancreatic cancer show higher sulfated HSPGs indicating a lack of Sulf1, but upon metastasis sulfation of HSPGs is reduced. Corroborating patient data were mouse tumor in vivo studies of Sulf1 overexpressing Panc-1 cells showing decreased growth, but increased local invasiveness. ## Other Cancers In vivo studies were used to investigate HSulf1 and 2 in myeloma. Myeloma cells overexpressing Sulf1 and 2 were subcutaneously injected in severe combined immunodeficient (SCID) mice. Enhanced Sulf expression markedly inhibited growth of these tumors with respect to the control. Again, FGF-2 signaling and subsequent phosphorylation of ERK was attenuated in vitro by both Sulf1 and Sulf2 expression. Sulf1/2 expression resulted in more ECM (collagen fibril deposition) than control tumors, which may be another mechanism by which Sulfs slow down tumor growth. The authors also find Sulf1/2 specifically acts on HS-GAGs on the surface of tumor cells and not in the surrounding stroma, which consequently acts to block FGF-2/FGFR/HS ternary complex formation and inhibition of a downstream signal. Squamous cell head and neck carcinoma (SCCHN) has three cell lines lacking Sulf1 expression. Transfected-in Sulf1 expression reduces FGF-2 and HGF-mediated phosphorylation and activation of ERK and phosphatidylinositol 3'-kinase (PI3K)/Akt pathways. Without these active pathways, a marked decreased in proliferation and mitogenecity is observed. Sulf1 expression even attenuates cell motility and invasion mediated by HGF, implicating Sulf1 loss in metastasis. # Animal models In addition to cancer, Sulf1 and Sulf2 were studied with respect to normal development including neural, muscle, vasculogenesis and skeletal development. Recently, much of what is known was from studies on Sulf1/2 knockout mice. ## Skeletal Development Through common genetrapping mechanisms, homozygous MSulf2 mice were created to assess the in vivo phenotypic traits. Strain specific nonpenetrant lethality resulted (48% fewer than expected), pups were smaller, and some lung defects were observed, but MSulf2-/- were largely as healthy and viable as wild type litter mates. MSulf2 nulls indicate MSulf1 and MSulf2 may have overlapping functions in regulating sulfation patterns in HSPGs. Given that MSulf2 null mice did not present major abnormal phenotypes double MSulf1/2 knockouts were generated. Again, MSulf1 and MSulf2 nulls individually did not display damaging phenotypes; however MSulf-/-;MSulf2-/- mice showed highly penetrant perinatal lethality. However, some double null mice survived into adulthood, and displayed smaller stature, skeletal lesions, and unusually small but functioning kidneys. The skeletal lesions (axial and appendicular skeleton showing decreases in ossified bone volume; sternal fusion and defective basisphenoid patterning) display similar phenotype to heparan sulfate 2-O-transferase (Hs2st)-deficient mice, BMP deficient mice and hypermorphic Fgfr1 and 3 mice. This provides evidence that Sulf1 and 2 is linked to HS modulation effecting BMP and FGF. In addition, this confirms that Sulf1 and 2 perform overlapping functions, but are needed for survival. Further studies on MSulf1-/-;MSulf2-/- mice extended the role of Sulfs in skeletal development. Double nulls displayed reduced bone length, premature ossification, and sternum and tail vertebrae fusion (Ratzka, Kalus et al. 2008). Also, the zone of proliferating chondrocytes was reduced by 90%, indicating defects in chondrogenesis. The important role Sulf1 and Sulf2 in skeletal development is not surprising given its regulation of bone-related growth factors. For example, QSulf1 reduces specific HS 6-O sulfation which releases Noggin, an inhibitor of bone morphogenetic protein (BMP), allowing cells to become BMP-4 responsive. Therefore, this directly links Sulf1 to the complex developmental patterning mediated by BMPs. Wnt signaling also is regulated by QSulf1. Investigators found lowered Wnt activation through the Frizzled receptor in the absence of QSulf1 expression in non-expressing embryonic cells. 6-O sulfate HS binds with highly affinity to Wnt, abrogating receptor activation. QSulf1 is required to desulfate 6-O chains, not entirely releasing Wnt but lowering the affinity with HS. This low affinity complex then binds and activates the Frizzled receptor. Additional studies emphasized the role of Sulfs in chondrogenesis. The role of QSulf1 was determined in quail cartilage development and joint formation because of its association with chondrogenic growth factor signaling (Wnt and BMP). Sulf1 was expressed highly in condensing mesenchyme and, in cell culture, caused prechondrocytes to differentiate into chondrocytes, indicating QSulf1 is needed for early chondrogenesis. QSulf1 displayed perichondrial staining during early development but was downregulated during later stages of development. In addition, QSulf1 shows transient expression in the early joint line followed by its rapid loss of expression in later stages of joint development, suggesting it would have an inhibitory effect in later joint development. Because Sulfs were important in normal chondrogenesis, they were investigated in cartilage diseases. Expression patterns of Sulf1 and Sulf2 were determined in normal and osteoarthritic (AO) cartilage. Both Sulf1 and Sulf2 showed enhanced expression in OA and aging cartilage. Given several HSPGs (perlecan, syndecan 1/3, glypican) are upregulated and growth factor signaling through FGF-2, Wnt, BMP, and Noggin are modulated in OA, Sulfs and the modifications of HS may mediate an entirely new level of control over OA development. ## Nervous System Development Sulf null mice and other model systems implicated Sulfs in other developmental and disease systems. For example, studies detected esophageal defects in surviving MSulf-/-;MSulf2-/- adult mice. Specifically, esophagi had impaired smooth muscle contractility with reduced neuronal innervation and enteric glial cell numbers. It was postulated to be mediated by decreased glial-derived neurotrophic factor (GDNF), which is responsible for neurite sprouting in the embryonic esophagus. Sulf expression is not obligatory for GDNF signaling, but it does enhance the signal greatly. MSulf1 and 2 are believed to decrease 6-O sulfation, releasing GDNF from HS to bind and activate its receptor, thereby mediating its effects on esophageal innervation. Sulf1 even functions in basic neural development. Sulf1 modulation of HS chains sulfation is critical in nervous system development. Specifically, Sufl1 expression leads to the switch of ventral neural progenitor cells toward an oligodendroglial fate by modulating Shh distribution and increasing signaling on apical neuroepithelial cells. ## Muscle Development and Other Regulation Sulf1 and 2 also display regulation over muscle development, angiogenesis, leukocyte rolling and wound healing. In adult mice, Sulf1 and Sulf2 have overlapping functions in regulating muscle regeneration. Functionally, Sulfs cooperatively desulfate HS 6-O present on activated satellite cells to suppress FGF2 signaling and therefore promote myogenic differentiation to regenerate muscle. Because of this role, Sulfs may have a direct role in diseases such as muscular dystrophy. QSulf1 was used as a tool to either decrease sulfation of HS or increase sulfation by employing a dominant negative QSulf1 (DNQSulf1). Vascular smooth muscle cells (VSMC) are highly influenced by degrees of HS sulfation. Overexpression of QSulf1 decreased adhesion, and increased proliferation and apoptosis of VSMC, while DNQSulf1 also decreased adhesion and increased proliferation, apoptosis, migration and chemotaxis of VSMC. Displaying cell specific effects, both overexpression of Sulf1 and DNQSulf1 increased ERK1/2 phosphorylation in VSMCs, a different response from cancer cell lines. Essentially, these experiments display that a fine-tuned 6-O sulfation pattern is needed for proper function of VSMCs. Sulf2 was investigated with respect to angiogenesis in a chick model. In contrast to Sulf1, Sulf2 actually induced angiogenesis in a chick chorioallantoic membrane assay. Sulf2 was measured for its ability to modulate binding of growth factors to trisulfated disaccharide motif heparin and HS. Sulf2 inhibited both pre- and post-binding of VEGF165, FGF-1, and SDF-1, a HS-binding chemokine, to both heparin and HS. Investigators hypothesize that Sulf-2 may mobilize ECM-sequestered angiogenic factors, increasing their bioavailability to endothelial cells that express the appropriate receptors. Investigators found that HSPGs such as perlecan and collagen type XVIII are modified during human renal ischemia/reperfusion, which is associated with severe endothelial damage. Vascular basement membrane (BM) HSPGs are modified to bind L-selectin and monocyte chemoattractant protein-1 (MCP-1) during leukocyte infiltration. Specifically, they require 6-0 sulfation to bind HS chains. The authors show evidence and propose that Sulf1 is usually present on microvascular BM but is downregulated to allow resulfation of 6-O HS for binding of L-selectin and MCP-1. This in turn implicates Sulf1 in human renal allograft rejection which is highly dependent upon HSPG function in peritubular capillaries. Finally, in a transcriptome wide assay in chronic wound, fortyfold higher expression Sulf1 was noted in wound-site vessels. This increase was attributed to its ability to inhibit angiogenesis as it had in breast cancer models.

Echogenic intracardiac focus # Overview Echogenic intracardiac focus (EIF) is a small bright spot seen in the baby’s heart on an ultrasound exam. This is thought to represent mineralization, or small deposits of calcium, in the muscle of the heart. EIFs are a found in about 3-5% of normal pregnancies and cause no health problems. EIFs themselves have no impact on health or heart function. Often the EIF is gone by the third trimester. If there are no problems or chromosome abnormalities, EIFs are considered normal changes, or variants. # Association with birth defects Researchers have noted an association between an EIF and a chromosome problem in the baby. Types of chromosome problems that are occasionally seen include Trisomy 18 or Trisomy 21 (Down syndrome). In the case of an isolated EIF, and no other ultrasound findings, some studies show that the risk for a chromosome abnormality is approximately two times a woman’s background risk. Other studies report up to a 1% risk for Down syndrome when an EIF is seen on a second trimester fetal ultrasound exam. # A clue to chromosome problems An EIF is one clue, which contribute to the chances of finding a chromosome problem. Generally the risks are low if there are no other risk factors. Many babies with chromosome problems do not show any signs on ultrasound. Other factors are discussed in counseling include: - Mother's age at the expected date of delivery - The results of the Expanded AFP blood triple test - Evidence of other "fetal findings" seen at on the ultrasound that suggest a chromosome problem. # Options Genetic counseling is recommended to give you more information about the EIF, to answer your questions and concerns, and go over the options available to you. Amniocentesis is a test to check a baby's chromosomes. A small amount of amniotic fluid, which contains some fetal cells, is removed and tested. Amniocentesis is very accurate; however, there is a risk of miscarriage of 1 in every 200 amniocentesis tests performed. Results take about two weeks. A normal amniocentesis result means the EIF is not significant and there would be no other concerns about it. # Summary An EIF in the fetal heart may increase the chance for the baby to have a chromosome problem. It does not affect the development of the baby or the function of the heart. If the baby has normal chromosomes, there would be no associated problems to be concerned about. No special treatment or tests are needed at delivery. It is important to remember that chances are strongly in your favor of a normal outcome in this pregnancy, but with this additional clue, you are entitled to further counseling and testing options.

Adult cardiac surgery and the COVID-19 pandemic: Aggressive infection mitigation strategies are necessary in the operating room and surgical recovery ## Central message Aggressive infection mitigation strategies are necessary to safeguard our patients and healthcare workers during the COVID-19 pandemic. The Centers for Disease Control and Prevention (CDC) recently published recommendations for the care of patients undergoing surgical procedures during the COVID-19 pandemic.Additional modifications provided by the American College of Surgeons offer further guidance for surgical patients and personnel.Both organizations have recommended significantly reducing or stopping elective cases and implementing logical, tiered general precautions. The Society of Thoracic Surgeons COVID-19 Task Force and the Workforce for Adult Cardiac and Vascular Surgery published tiered patient triage guidance. [bib_ref] on behalf of The Society of Thoracic Surgeons COVID-19 Task Force and..., Haft [/bib_ref] Other suggestions from the American College of Surgeons to enhance safety for healthcare workersin the context of COVID-19 include the following: 1. Consider nonoperative management whenever it is clinically appropriate for the patient. 2. Complete testing as close to the planned operative date (preferably <48 hours) to lessen the risk that a patient becomes positive while waiting for a surgical procedure. 3. Avoid emergency surgical procedures during off hours, when possible, due to limited team staffing and the potential lack of optimal specialty specific expertise. 4. Perform aerosol-generating procedures (AGPs) [bib_ref] Aerosol generating procedures and risk of transmission of acute respiratory infections to..., Tran [/bib_ref] in confirmed or suspected COVID-19 patients while practicing enhanced droplet/contact precautions, including an N95 mask, eye protection, gown and gloves, or a powered air-purifying respirator. Examples of known and possible AGPs include: a. Intubation, extubation, bag mask ventilation, noninvasive ventilation (continuous positive airway pressure and bilevel positive airway pressure), airway suctioning, nebulizer therapies, bronchoscopy, chest tube insertion, thoracotomies, and pleural procedures b. Electrocautery of blood or any other body fluids 6 c. Endoscopy 5. Defer nonurgent cardiovascular testing. 6. Distinguishing COVID-19 from other respiratory infections will be challenging; therefore, interventions will need to be applied broadly and not limited to patients with confirmed COVID-19.While helpful, these guidelines do not provide the granular guidance needed to address important aspects of the surgical management of cardiac surgical patients. In particular, there will remain a certain volume of patients who will still require urgent and emergent operations during this pandemic. At time of writing this document, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus associated with COVID-19 disease, has been associated with at least a 6% mortality in the United States in those patients with a confirmed diagnosis.The virus is well equipped with several virologic, epidemiologic, and clinical features that have contributed to its ability to rapidly spread through a global population. Specifically, a substantial number of asymptomatic or presymptomatic infections, with or without mild symptoms, are key to its effective dissemination throughout populations, including to healthcare providers. [bib_ref] Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV-2), Li [/bib_ref] At times of documented or assumed community spread of COVID-19, it is reasonable to suspect that all patients could be carriers of the virus. As such, all patients should be considered COVID-19 suspects, regardless of testing availability or results, and all patients should be treated equally with precautions similar to those used in COVID-19-confirmed cases. This approach is similar to the concept of universal precautions. This level of safety may not be required if community transmission and the burden of cases is low in specific areas. However, to minimize infectious risk to healthcare providers of patients undergoing cardiac surgical procedures in the preoperative, intraoperative, and postoperative period, additional detailed protective strategies are suggested. These are guidance recommendations during a pandemic surge for all patients until the supply chain for personal protective equipment (PPE) is restored and local COVID-19 disease burden is substantially reduced. ## Guidance recommendations 1. Patients should be transferred directly to the operating room (OR), without stopping in the preoperative or postanesthesia care unit areas, to minimize exposure to other patients, staff, and other environments. 2. "COVID-19 precautions" signs should be posted on all doors to the OR suite to inform staff of potential risks and minimize exposure. 3. The OR should remain positive pressure, but the surrounding rooms (ie, anteroom[s]) must maintain a strict negative pressure ventilation system at more than À2.5 Pa at 12 or more air changes per hour. 9 4. All OR staff are required to practice enhanced droplet and contact precautions in the OR at all times. This includes the use of N95 respirator, eye protection, gown, and gloves. Given the possibility of false-negative testing (10%-30%), [bib_ref] Evaluating the accuracy of different respiratory specimens in the laboratory diagnosis and..., Yang [/bib_ref] [formula] Ig ¼ immunoglobulin OR ¼ operating room PPE ¼ personal protective equipment SARS-CoV-2 ¼ severe acute respiratory syndrome coronavirus 2 TEE ¼ transesophageal echocardiography [/formula] Anesthesiologists recommends that all anesthesia professionals should use PPE appropriate for AGPs for all patients during all diagnostic, therapeutic, and surgical procedures when working near the airway.We would broaden this recommendation to include all OR personnel. 5. If N95 masks are to be reused (though not optimal) the CDC recommends a 5-day period of drying 12 or preferably decontaminated using ultraviolet germicidal irradiation, vaporous hydrogen peroxide, or moist heat by autoclaving. 12,13 6. If a powered air-purifying respirator is used as an alternative to an N95 respirator and eye protection, practitioners should be cautioned that these devices may reduce the clarity of surgical loupes and positioning of headlights. 7. A donning-and-doffing-trained observeris highly recommended because most nosocomial spread of COVID-19 occurs during this critical period. [bib_ref] Self-contamination during doffing of personal protective equipment by healthcare workers to prevent..., Suen [/bib_ref] Ongoing donning-and-doffing simulation training should be regularly performed for continual refinement of safety processes. 8. Limit entry/exit to a single OR entrance. Keep all OR doors closed as much as possible, and limit staff entry/reentry to keep OR pressures and air exchanges regulated. 9. Before AGPs are performed, OR personnel must ensure that no more than the minimal number of staff required to safely achieve the procedure are present in the room. 10. During induction and endotracheal intubation, it is recommended that the anesthesiologist: a. Be the most experienced available operator with the highest probability of first-pass intubation. b. Limit the number of staff in the OR to the minimum needed to safely intubate (1 anesthesiologist plus 1 or 2 assistants). c. At the discretion of the anesthesiologist, video laryngoscopy may be chosen over direct visualization to decrease the risk of droplet transmission. d. Preoxygenate with 100% inspired oxygen and avoid bag-mask ventilation unless absolutely necessary. 11. After AGPs, including intubation, additional OR personnel should wait 30 minutes before entering the room (this is dependent on the efficiency of the air exchange in each OR suite; see point 3 above). 12. Intraoperative staffing for the surgical case should be minimized to the minimal number needed to safely and efficiently complete the procedure. [bib_ref] N95 mask decontamination using standard hospital sterilization technologies, Kumar [/bib_ref]. Staff relief for breaks should be provided only as necessary to preserve PPE and decrease the number of staff exposed and reentries. 14. Smoke evacuation of electrosurgical devices should be used to minimize staff exposure to surgical smoke. [bib_ref] Awareness of surgical smoke hazards and enhancement of surgical smoke prevention among..., Liu [/bib_ref] 15. Patients should preferably recover in a negativepressure isolation room when resources permit (in the postanesthesia care unit or intensive care unit). If negative-pressure isolation rooms are unavailable, consider early recovery in the OR before transfer to a single patient room. 16. After the patient has left the OR, the OR should be closed for an appropriate standoff period to achieve greater than 99.9% aerosol clearance. The amount of time that aerosols stay suspended in the air will depend on a number of factors, including the size of the room, the number of air changes per hour, how long the patient was in the room, whether the patient was coughing or sneezing, and whether an AGP was performed. General guidance on clearance rates under differing ventilation conditions is available from the CDC.17. After the standoff period, the OR suite must be cleaned using routine procedures with United States Environmental Protection Agency-approved hospital disinfectant. 18. Operations should be performed by the most experienced available surgeons and assistants to limit exposure time in the OR. Junior residents and other learners should not be exposed unless absolutely necessary. 19. Strong consideration to surgical approach and technique must be considered to optimize patient outcomes while minimizing exposure risk to providers. Use of laparoscopic or video-assisted thoracoscopic procedures should be avoided when possible due to risk of aerosolization from CO 2 insufflation systems with inadvertent lung injury. 20. Limit all routine preoperative and postoperative laboratory testing, imaging, and procedures to minimize personnel exposure. 21. COVID-19 repeat testing is only required in postoperative patients when symptoms or signs of COVID-19 develop. Rapid COVID-19 testing is preferred when available. 22. In the event of cardiac arrest or other medical emergency, all patients must continue to be treated as suspected or confirmed COVID-19 cases. This requires strict adherence to enhanced contact and droplet precautions. No patient interaction should be permitted before full PPE is donned. This likely represents an uncomfortable paradigm shift for surgeons accustomed to "jumping into lifesaving patient interactions with little regard to infectious risk." 23. For a cardiac arrest in the intensive care unit, only 1 provider should provide cardiopulmonary resuscitation while medications are administered. Cessation of advanced cardiac life support is at the discretion of the provider, but prolonged resuscitative efforts should be avoided due to futility and risk. [bib_ref] In-hospital cardiac arrest outcomes among patients with COVID-19 pneumonia in Wuhan, Shao [/bib_ref] 24. Transesophageal echocardiography (TEE) in an intubated, anesthetized patient has never been demonstrated to generate aerosols. However, many societies have classified TEE as an AGP. Clinicians should weigh the necessity of placing a TEE in each cardiac surgical patient against the theoretical concern of generating aerosols. If performed, all staff should wear an N95 mask. The most experienced echocardiographer should perform the examination, including probe insertion and removal. 18 ## Covid-19 testing There is accumulating evidence indicating that a substantial fraction of COVID-19-infected individuals are asymptomatic. [bib_ref] Evidence of SARS-CoV-2 infection in returning travelers from Wuhan, China, Hoehl [/bib_ref] A study of skilled nursing facility residents infected with COVID-19 demonstrated that half were asymptomatic or presymptomatic at the time of contact tracing evaluation and testing. [bib_ref] Asymptomatic and presymptomatic SARS-CoV-2 infections in residents of a long-term care skilled..., Kimball [/bib_ref] In a population-based study in Iceland, 43% of the participants who tested positive reported having no symptoms. [bib_ref] Spread of SARS-CoV-2 in the Icelandic Population, Gudbjartsson [/bib_ref] A study of 215 pregnant women admitted for delivery in New York City found 15% were COVID-19 positive, 88% of whom were asymptomatic. [bib_ref] Universal screening for SARS-CoV-2 in women admitted for delivery, Sutton [/bib_ref] Virologic studies have demonstrated viral RNA and viable virus among persons with asymptomatic and presymptomatic infection. [bib_ref] Evidence of SARS-CoV-2 infection in returning travelers from Wuhan, China, Hoehl [/bib_ref] [bib_ref] Asymptomatic and presymptomatic SARS-CoV-2 infections in residents of a long-term care skilled..., Kimball [/bib_ref] [bib_ref] SARS-CoV-2 viral load in upper respiratory specimens of infected patients, Zou [/bib_ref] If a high-fidelity, rapid point-of-care testing system is available, providers could consider screening preoperative patients immediately before a surgical procedure if time permits within a 24-hour window, particularly in areas of high COVID-19 disease burden. Positive screening tests should lead to reconsideration of the risks and benefits of proceeding with the planned surgical procedure. These patients may be in the presymptomatic or early symptomatic phase of infection and are likely at heightened risk of adverse outcomes after an operative procedure. In a retrospective cohort study of 34 patients who were unintentionally scheduled for elective operations during the incubation period of COVID-19, the mortality rate was 20%. [bib_ref] Clinical characteristics and outcomes of hospitalised patients with COVID-19 treated in Hubei..., Liang [/bib_ref] However, negative screening tests must be interpreted with caution, particularly in the setting of (1) low pretest probability, (2) typically low viral titers in the asymptomatic phase, and (3) the possibility of false-negative results. If clinical suspicion for COVID-19 remains due to exposure history, active symptoms, high prevalence of circulating community infections, or other clinical factors, repeat testing may be indicated during the postoperative course. ## Serologic immunity After viral infections, an immunoglobulin (Ig) M immune response occurs, which then diminishes within a few weeks. The IgG and IgA immune response occurs simultaneously, producing more specific and longer-acting immunity.Testing patients' serostatus could be an important tool to determine whether patients have mounted prior immunity from natural infection, reducing the likelihood of current COVID-19 colonization. The prospect of testing providers for serologic immunity to COVID-19 is also promising if the presence of antibodies confers immunity to future infection, because providers with acquired immunity could be selected to care for COVID-19 suspected or confirmed patients. Unfortunately, serologic testing and capacity are currently limited and require further scientific evidence to support their use in screening healthcare workers. Important studies are underway to determine the pattern of antibody development after COVID-19 infection, whether antibodies confer immunity to future infections, whether specific antibody titers determine the level of protection, and the duration of conferred immunity. Similar coronavirus outbreaks demonstrated that survivors developed robust immunity after natural infection. The 2003 severe acute respiratory syndrome outbreak elicited an immunity that was protective for up to 3 years. [bib_ref] Duration of antibody responses after severe acute respiratory syndrome, Wu [/bib_ref] Until more data emerge supporting the widespread adoption of antibody testing, 29 strict infection prevention and control policies are required to enhance the safety of patients and providers. # Conclusions At the present time, we urge all healthcare organizations providing cardiac surgical procedures in regional environments of widespread COVID-19 disease to consider adopting these aggressive mitigation strategies (1) to create a safe environment that protects our patients from acquiring or transmitting COVID-19 and (2) to protect members of our surgical and postoperative provider teams. We all look forward to the near future when elective surgical procedures can be resumed as the threat of this virus wanes and capacity permits. However, until that time, and in an effort to hasten its arrival, the aforementioned protocols should become standard of care. Rakesh C. Arora has received an unrestricted educational grant from Pfizer Canada Inc.

The Occupational Safety and Health Act of 1970 emphasizes the need for standards to protect the health of workers exposed to an ever-increasing number of potential hasards at their workplace. To provide relevant data from which valid criteria and effective stan dards can be deduced, the National Institute for Occupational Safety and Health has projected a formal system of research, with priorities determined on the basis of specified Indices. It is intended to present successive reports as research and epidemiologic studies are completed and sampling and analytic methods are developed. Criteria and standards will be reviewed periodically to ensure continuing protection of the worker. I am pleased to acknowledge the contributions to this report on chromic acid by members of my staff, by Robert B. O'Connor, M.D., NIOSH consultant In occupational medicine, and by Edwin C. Hyatt, MIOSH consultant on respiratory protection. Valuable and constructive comments were presented by the Review Consultants on Chromic A d d and by the ad hoc committees of the Industrial Medical Association and of the American Academy of Industrial Hygiene. The NIOSH recommendations for standards are not necessarily a consensus of all the consultants and professional societies that reviewed this criteria document on chromic a d d . Lists of the NIOSH Review Committee members and of the Review Consultants appear on the following pages.# I. # RECOMMENDATIONS FOR A CHROMIC ACID STANDARD The Sampling and Analysis: Procedures for sampling and analysis of air samples shall be as provided in Appendices I and II, or by any method shown to be equivalent in precision, accuracy, and sensitivity to the methods specified. # Section 2 -Medical Medical surveillance shall be made available as outlined below for all workers occupationally exposed to chromic acid. Maintenance personnel periodically exposed during routine maintenance or emergency repair operations shall also be offered medical surveillance. (a) Preplacement and annual medical examinations shall include : A work history to elicit information on all past exposures to chromic acid and other hexavalent chromium compounds. A medical history to elicit information on condi tions indicating the inadvisability of further exposure to chromic acid, eg, skin or pulmonary sensitization, or a skin or mucous membrane condition that may promote response to chromic acid. (3) Thorough examination of the skin for evidence of dermatitis or chromic ulcers and of the membranes of the upper respiratory tract for irritation, bleeding, ulcerations or perforations. (4) An evaluation of the advisability of the worker's using negative-or positive-pressure respirators. Do not get in eyes, on skin, on clothing. Do not breathe dust or mist from solutions. In case of contact, immediately flush skin or eyes with plenty of water for at least 15 minutes. For eyes, get medical attention Immediately. Wash clothing before reuse, Use fresh clothing daily. Take hot showers after work, using plenty of soap. # (b) The following warning sign shall be affixed in a readily visible location at or near entrances to areas in which there is occupational' exposure to chromic acid. (1) For the purpose of determining the class of respirator to be used, the employer shall measure the atmospheric concentration of chromic acid in the workplace «ben the initial application for variance is made and thereafter whenever process, worksite, climate, or control changes occur which are likely to affect the chromic acid concentration. The employer shall ensure that no worker is being exposed to chromic acid in excess of the standard because of improper respirator selection or fit. (2) A respiratory protective program meeting the general requirements outlined in section 3.5 of American National Standard Practices for Respiratory Protection Z88.2-1969 shall be established and enforced by the employer. Unless eye protection is afforded by a respirator hood or facepiece, protective goggles or face shields impervious to chromic acid shall be worn at operations where chromic acid splashes may contact the eyes. (4) All protective equipment shall be maintained in a clean and satisfactory working condition. NIOSH estimates that 15,000 people are potentially exposed to chromic acid mist. # Historical Reports One of the first reports of injury to workers in this country from exposure to chromium compounds was in 1884 by MacKenzie. He reported that factory workers employed in the chambers where bichromate was made invariably developed perforation of the nasal septum, generally within a few days of exposure. The characteristic development of septal perforation was described in detail. Although destruction of the cartilage was reported to be very extensive in many cases, the external appearance of the nose was said to be unchanged. Other effects reported included ulceration of the turbinates and nasal pharynx, and inflammation of the lower respiratory tract. Perforation of the tympanic membrane was also reported, due either to passage of bichromates through the Eustachian tubes or to direct external contact. Reporting on 12 cases in two plating plants, Blair in 1928 described four electroplaters who experienced symptoms of a bad cold with coryza, sneezing, watery discharge from the eyes and nose, and itching and burning of the nose, especially when they left the plant and came in contact with outdoor air. Of these four men, one had a perforated nasal septum, one a large unilateral ulcer on the septum, and two had marked congestion of the nasal mucosa with hyperemia, swelling, mucoid discharge, and small ulcers. In this mortality study of employees from seven chromate plants with mixed exposures to trivalent and hexavalent chromium compounds, the crude death rate (ie, the death rate not adjusted for age) for lung cancer was 25 times greater than normal. This investigation was followed by others establishing an increased risk for lung cancer in workers in chromate plants. Effects on Humans Chromium is a naturally occurring trace element found in human tissues. Imbus et al reported normal levels of 2.65 yg/100 g of blood and 3.77 ^g/liter of urine. Schroeder et al reported the normal level in adult tissue in the United States to be 2.3 yg/g of ash in the kidney and 1.6 yg/g ash in the liver. Levels were higher in persons from other countries. The element was found in relatively high concentrations in all tissues of newborns (51.8 yg/g ash and 17.9 yg/g ash in the kidney and liver, respectively) but the concentration fell during the first two decades of life and was stable thereafter, except in the lungs. In the lungs, the chromium level was reported to be 85.2 yg/g ash in Infants. This decreased to a low of 6.8 yg/g ash during the second decade, after which the reported level gradually rose to 38.0 yg/g ash in the 70-80 year age group. Chromium affects glucose and lipid metabolism in animals as well as in man, and is an essential micronutrient in mice and rats. In workers occupationally exposed to mixed chromites and chromates in the chromate producing industry, the U.S. Public Health Service reported median blood chromium levels of 0.004 and 0.006 mg/100 ml blood for white and black workers, respectively. No overall mean or median was reported. Median urine levels of 0.043 and 0.071 mg/liter, respectively, were reported for white and black workers. Among similarly exposed production and maintenance workers, Mancuso The exposure levels of chromic acid were not measured by the investigator. One worker was exposed to the chromic acid mist for approximately four days while concentrating chromic acid by boiling the acid in large vats. The first symptoms were coughing and wheezing, followed by severe frontal headaches, dyspnea, pain on deep inspiration, fever, and loss of weight. After six months the worker had improved with respect to weight and cough but still had chest pains on deep inspiration. A bronchoscopic examination 6 months after exposure "revealed that the tracheal mucosa and the mucosa of the entire tracheobronchial tree was hyperemic and somewhat edematous." Eleven months after exposure, the worker still had complaints of Infrequent chills, cough, and mild pains located in the anterior part of the chest. The second worker, though working at the same operation, was exposed for only one day. He stated that he had no immediate ill effects from inhalation of the mist, but during the following three or four days hoarseness developed, with a cough productive of whitish mucoid sputum. A chest X-ray, hematologic studies, and urinalysis produced no abnormal results, but during the following three months the patient became anorexic and noted a gradual loss of 20 to 25 Pascale et al in 1952 reported five cases of hepatic injury apparently due to exposure to chromic acid from plating baths. A person, who had been employed five years at a chromium plating factory, was hospitalized with jaundice and was found to be excreting significant amounts of chromium. Her lungs and cardiovascular system were normal. A liver biopsy showed histological changes resembling those found in toxic hepatitis. To investigate the possibility that the liver damage was of occupational origin, eight fellow workers were screened for urinary chromium excretion. Four of these were found to be excreting significant amounts and were examined in more detail. In three workers who had been exposed to chromic acid mists for 1 to 4 years, liver biopsies and a series of twelve hepatic tests showed mild to moderate abnormalities. No liver biopsy was taken from the fifth worker, who had been removed from further exposure because of nasal ulceration after 6 months at the plating bath. Only one of his liver function tests indicated a borderline abnormality. The urinary excretion of chromium (2.8 and 2.9 mg/24 hours) by the two workers employed four years was greater than the excretion (1.48 mg/24 hours) by the worker employed five years who suffered the greatest liver damage. The lowest urinary chromium excretion (0.184 mg/24 hours) was measured in the fifth worker, the individual with least exposure. All five exhibited some signs of damage to the nasal mucosa. This plus the levels of urinary excretion suggests that exposures were significant, but no environmental data were reported. # Epidemiologic Studies No epidemiologic data are available on the incidence of pulmon ary cancer in workers exposed only to chromic acid. The epidemiologic data that are available pertain to workers In the chromate-producing industry. These workers were subject to mixed exposures, and these data have only indirect and limited application to chromic acid exposures. The first report of lung cancer from exposure to chromium was given in 1932 by Lehmann. He reported two cases of workers with lung cancer out of several hundred workers who had been employed in a chrornate plant in Germany. No information was given on the length of exposure or on the nature and airborne concentration of the exposure to chromium compounds. Lehmann did not consider these two cases to be occupationally related. Machle and Gregorius gave the first report on the incidence of cancer of the respiratory system in the chromate industry in the United States. The workers had been exposed to chromite ore and a mixture of trivalent and hexavalent chromium compounds. Available records from seven chromate plants for the preceding 10-15 years (1933)(1934)(1935)(1936)(1937)(1938)(1939)(1940)(1941)(1942)(1943)(1944)(1945)(1946)(1947)(1948) were studied. Of the 193 deaths in all plants, 66 (34.2%) were due to cancer of any type or at any site, a rate over twice that for a control industrial group. This increase was attributable to an excessive proportion of deaths from cancer of the respiratory system. Lung cancers comprised 60% of all cancers as compared to an expected rate of 9%. In five of the seven plants, (no deaths due to lung cancer were recorded in two plants) lung cancer rates varied from 13 to 31 times normal. The mean duration of exposure prior to onset was 14.5 years. One plant (plant C in Machle and Gregorius ) with no cancer deaths was small and no deaths from any cause were seen among its workers during the period covered. The second was one of two plants (D1 and D2 ) in the study owned by a single company. In plant D2 there were 33 deaths in 1,853 male-years (a term used by the authors to Indicate that only males were included in the group studied) of exposure. Four of the 33 deaths (.12.1%) were cancer deaths; none were cancer of the respiratory system. In contrast, in plant Dl there were 29 deaths in 2,491 male-years of exposure, of which five were due to lung cancer. These five deaths represented 17.4% of all deaths, or 71.4% (5 of 7) of all cancer deaths. Although the best available data had been used, the Machle and Gregorius report The percentage of lung cancer patients who were employed at the chromate-producing plant was compared with the percentage of the employed male population of Baltimore who were employed at the plant. Statistical analysis again indicated that the percentage of chromate workers in the lung cancer series was significantly higher than the percentage of chromate workers in the employed male population of Baltimore. This study therefore confirmed the earlier conclusions of Machie and Gregorius that the number of deaths due to cancer of the lungs and bronchi was greater in the chromate-producing Industry than was normally expected. Mancuso and Hueper in 1951 reported on a study of occupational cancer in workers in a chromate plant. The workers were exposed to a mixture of trivalent and hexavalent chromium compounds including chromic acid. Of 33 deaths from all causes, nine (27.2%) were from all types of cancers. Six of these (18.2% of all deaths) were from cancer of the respiratory system. The mean latent period was 10.6 years. In comparison, out of 2,931 deaths in Lake County, Ohio, In which the plant was located, 34 were due to lung cancer. The ratio of lung cancer to total deaths in the chromate plant was 17 times that of Lake County. This was followed with a report by Mancuso on the clinical and toxicologic aspects of 97 workers examined in a chromateproduction plant: 63% showed perforations of the nasal septum or ulcers of the mucosa, 87% had chronic rhinitis, 42% had chronic phar yngitis, 10% had hoarseness, and 12% had polyps or cysts. Thirtyseven percent of the 97 examined had some involvement of the nose, throat, and sinuses. A total of 17.5% of those given gastrointestinal X-ray exami nations had evidence or ulcers, gastritis, or gastrointestinal tumor. In comparison, X-ray examinations of a group of cement workers showed that 4 of 41 (9.8%) had similar evidence. The author stated "workers The great majority of these were air samples, but material and settled dust samples were also collected. It was found that the milling, roasting, and leaching processes generated dusts containing chromite ore, soda ash, roast, residue, and of a mask, petrolatum in the nostrils, and nasal douching was judged to be the most effective protection. The authors concluded that the prevalence of nasal perforation was not a valid index of the prevalence of pulmonary carcinoma. Ten of the 897 chromate workers examined were diagnosed as having bronchogenic carcinoma (3 of the 10 had been diagnosed before the survey). The mean age of these 10 workers was 54. 5 Expected deaths from the selected causes were determined from the agecause specific mortality rates for the U.S. civilian male population. No data were presented on levels of worker exposure to chromates. All of the preceding reports 16,32] Bidstrup and Case reported a follow-up study of the remaining 723 workers, conducted almost six years after the first study. In the follow-up, it was found that 217 workers had left the industry and were lost to the follow-up. A total of 59 men were known to have died, 12 of these by lung cancer. This compared to 3.3 expected lung cancer deaths, or an incidence of 360% of expected. The difference was statistically significant, but as the authors pointed out, by the time all the men at risk have lived their life span, the lung cancer increase probably will be found to be very much higher. The possi bility that the increase was due to nonoccupational factors such as diagnostic bias, place of residence, social class, or smoking habits was examined and discarded. It was not possible to form an opinion about the identity of the occupational carcinogen. The chromate workers in the above studies 32] had exposures to a mixture of trivalent and hexavalent chromium compounds of which chromic acid was only a minor part. The workers were exposed to chromite ore, chromlte-chromate intermediates and chromates as well as trace metals and minerals associated with the processing of the chromite ore. These studies suggest that exposure to the roasted chromite ore complex may be important as a causative agent of the lung cancer observed In chromate workers. In the literature, there is no direct evidence that exposure to chromic acid per se at the measured concentrations and under the conditions of industrial exposure has led to cancer. However, no study of this nature has been undertaken. More definitive data are needed on this subject. Bloomfield and Blum in 1928 reported on a study of health hazards in chromium plating. In the study 19 workers were examined General room ventilation was provided through the use of room fans and opened windows. Four of the nine workers examined with exposure times ranging from 2 to 12 months had perforated nasal septa, three workers with exposure times ranging from 1 to 10 months had ulcerated nasal septa, and two workers with exposure times of 0.5 and 9 months, respectively, had moderate injection of the nasal septa. The air sampling was done at the breathing zone level near where the worker stood. In 1972 Gomes made a study of the incidence of cutaneousmucous lesions in workers exposed to chromic acid in the State of Sao Paulo, Brazil. He found that only 50% of the industries used exhaust protection and that the threshold limit for workers in electroplating with hot chromic acid was frequently surpassed. Clinical examination of the 303 workers exposed to chromic acid revealed that 24% had perforated nasal septa and 38.4% ulceration of the same. Together, these lesions of the nasal septum affected more than 50% of the workers. More than 50% of the workers examined showed ulcerous scars not only on the hands, but also on forearms, arms, and feet. Ulcerous scars on the feet were due to working without boots and the wearing of Japanese type sandals. # Animal Toxicity In order to study in animals the reported cancer hazard due to chromium, Hueper attempted to identify a species and tissue sensitive to the carcinogenic action of chromium or its compounds. Chromium and chromite ore were introduced in a powdered form suspended in two different vehicles (lanolin, gelatin) by various routes (in the femur, intrapleural, intraperitoneal, Intravenous, Intramuscular, Intranasal sinus) into mice, rats, guinea pigs, rabbits, and dogs. Results were equivocal at best as to evidence supporting a carcinogenic action of metallic chromium and chromite ore. Only in rats were tumors observed which might have been causally related to the chromium deposits. In the series with thigh implants, three developed tumors (one benign) remote from the implant. This suggested to the investigator that the chromite ore roast contained carcinogenic material, possibly the water insoluble-acid soluble chromium compounds present. The author concluded that the carcinogenic action of chromium was dependent on the solubility of the compound and the amount present, stating that if hexavalent chromium in the form of chromate ion is available in too large a dose, acute effects result, but that a smaller dose can result in malignancy. These results and conclusions were corroborated by Roe and Carter who injected rats intramuscularly with calcium chromate in arachis oil. Twenty once-weekly injections were given. The first two Injections contained 5.0 mg of calcium chromate, but signs of severe local Inflammation developed, so the dosage in the last 18 injections was 0.5 mg. Of 24 test rats, 11 developed spindle cell sarcomas and seven developed pleomorphic sarcomas at the injection site. No tumors were seen in 16 controls. Laskin et al in 1969 reported studies of selected chromium compounds in a cholesterol carrier using an intrabronchial implanta tion technique. Compounds under investigation included chromic chromate, chromic oxide, chromium trioxide, calcium chromate, and process residue. Pellets were prepared from molten mixtures of materials dispersed in equal quantities of cholesterol carrier. These studies included materials of differing solubilities and valences, and have involved over 500 rats that were under observation for periods of up to 136 weeks. Lung cancers that closely simulate lung cancer in man were found in these studies. With the calcium chromate, eight cancers were found in an exposed group of 100 animals. Six of these were squamous cell carcinomas. In all the experimental groups except the one exposed to chromium trioxide, there was evidence of atypical squamous metaplasia of the bronchus. In the 100 rats implanted with chromium trioxide, two tumors were observed, both hepato-cell carcinomas. Since these studies Implicated calcium chromate as a lung carcinogen, inhalation studies using this compound were begun. The study is not yet completed, but preliminary results suggest a carcinogenic action in rats after chronic exposure to aerosols at a concentration of 2.0 mg/cu m. These results may be significant for the human experience in the chromate-producing industry. As noted by this researcher, calcium chromate exists in the residue step to the extent of 3% in no-lime roasts and at significantly higher levels when lime is used. # Correlation of Exposure and Effect Only five studies are available which report both the effects in man of chromic acid exposure and atmospheric levels of chromic acid. 29,41] All these reported the atmospheric levels as measured at the time of the study. Consequently, all share a common weakness, in that effects were reported which were cumulative effects of past exposures to chromic acid concentrations which may have been different from the levels reported. Nevertheless, limited correlations can be drawn. In the study by Bloomfield and Blum, six plating plants were surveyed and the atmospheric concentration of chromic acid was determined in each, based on a total of 39 air samples. Using these data and the occupational histories of the workers, the investigators estimated the amount of chromic acid to which some workers were exposed daily during the time employed in the plating room. When the worker had been employed only a short time, "the estimated degree of exposure was more than an approximation" In the authors' opinion, since the ventilation system in use at the time of the purvey had been in use throughout the individual's employment. Exposures were estimated for 23 workers who were given physical examinations. Four of these were controls with no known exposure to chromic acid. Estimated exposures for the remaining 19 ranged from 0.12 to 5.6 mg/cu m. Six platers were exposed to chromic acid estimated at a level of 0.12 mg/cu m. Employment had ranged from one week to seven months. All had inflamed mucosa and three had nosebleed. The exposures in the past may have been different from those observed at the time of the study, but the data do indicate that distinct Injury to the nasal tissues can result after relatively short exposures. Some of these six platers were exposed such a short time that their experience strongly suggests that, assuming an accurate estimate was made, a concentration of 0.12 mg/cu m can cause inflammation of the nasal mucosa and nosebleed. This was the conclusion of the authors, who stated that continuous daily exposure to concentrations greater than 0.1 mg/cu m is likely to cause definite injury to the nasal tissues. Because these reports all fail to give long-term environmental data, the effects observed cannot be directly related to the en vironmental data reported. Nevertheless, the five papers consistently illustrate that adverse effects can result after relatively short periods of employment and therefore short periods of exposure to 42 chromic acid. The papers also consistently Indicate that nasal Irritation does occur at atmospheric concentrations of 0.1 mg/cu m and may occur at lower levels. # IV. ENVIRONMENTAL DATA AND ENGINEERING CONTROLS Measurements of atmospheric concentrations of chromic acid around Industrial operations before and after controls were Instituted attest to the marked effect of controls In lowering the airborne levels of this contaminant. In 1928, Bloomfield and Blum studied six plating plants with varying degrees of ventilation control and changing operating conditions. In one plant, concentrations were as high as 6.9 mg of chromic acid per cubic meter of air with no ventila tion in use while plating with a current density of 300 amperes per square foot. However, at the same current density but with ventilation operating at an air velocity of 1700 feet per minute at the face of the slot, there was no detectable chromic acid in the workers' breathing zone. In order to insure a reasonable safety factor, they recommended a lateral slot-type exhaust system operating at an air velocity of 2,000 fpm at the face of the slot, drawing air no more than 18 inches laterally. They also recommended that the exhaust slots be flush with the top of the tank and that the plating solution be at least 8 Inches below the top of the tanks to allow ample time for the mist to be directed to the exhaust slot. # Basis for Recommended Environmental Standard Industrial exposure to mixed chromite and chromate compounds has been shown to cause ulceration of the skin, dermatitis, ulceration and perforation of the nasal septum, inflamed mucosa, irritation of the conjunctiva, and cancer of the lung. 32] Other effects reported as a result of mixed exposures include nasal mucosal polyps, chromitotic pneumoconiosis, chronic rhinitis, sinusitis, mucosal polyps and hydrops of nasal sinuses, inflammatory and ulcerative conditions of the gastrointestinal tract, and, often, an imbalanced ratio of the formed elements of the blood as well as lengthened bleeding time. Occupational exposure to chromic acid has been shown to cause ulceration of the skin, ulceration and perforation of the nasal septum, 30,31] inflamed or bleeding nasal mucosa, and ulceration or congestion of the turbinates. Erosion and discoloration of the teeth has been attributed to chromic acid exposure as has discoloration of the skin. Apparent liver damage has been reported, but other reports have indicated there was no evidence either of hepatic or of renal damage after acute and chronic exposure. An increased incidence of lung cancer has not been found reported from exposure to chromic acid alone. In one epidemiologic study of seven chromate plants, it is suggested that the carcinogen is a monochromate found in the process ing of the chromite ore. In that study, the crude death rate (ie, the death rate not corrected for age) from cancer of the lung was 25 times higher than normal, but all observed lung cancer deaths were confined to five of the seven plants. One plant was quite small and there were no deaths among its employees during the nine years surveyed. There were no lung cancer deaths in another plant which was one of two plants in the study owned by a single company. The worker populations of the two plants were "similar with respect to age distribution, exposure history, color, geographic location, and were not greatly different in size." There was, however, an obvious difference in exposure, since one plant produced sodium bichromate from chromite ore, while the second plant produced chromic acid and basic chromic sulfate from the sodium bichromate. The incidence of death by lung cancer was 18 times normal in the plant producing sodium bichromate, while there were no lung cancer deaths in the plant processing the bichromate. Monochromates were suggested as the etiologic agent on the basis that the lung cancer was widely distributed in the first plant among all occupations entailing exposure to monochromates. Thus, there is ample evidence that workers with mixed exposure in the chromate-producing industry have been at Increased risk of lung cancer. 32] Unfortunately, no epidemiological study of workers exposed only to chromic acid has been undertaken. There is reason to suspect other chromium compounds as the carcinogens responsible for the increased lung cancer observed in chromate plants. The chromite ore Itself has been suggested as the etiologic agent, as have the monochromates, and Intermediate water insolubleacid soluble compounds. The animal studies by Hueper, Payne, Hueper and Payne, and Roe and Carter suggest that the etiologic agent is a moderately soluble chromate which can be slowly released from a tissue "reservoir" in amounts which are not sufficiently toxic to cause necrosis. Calcium chromate has been implicated as a lung carcinogen by Laskin et al and by Kuschner. Hueper has indicated the risk of cancer is negligible when chromic acid is used medicinally. This judgment was based in part on the "extreme rarity of such sequelae" to chronic ulcerative defects of the skin and nasal mucous membranes in workers having occupational contact with chromic acid mist and chromates. Therefore, while there is no positive evidence that chromic acid in the workplace has contributed to an increase in cancer, neither is there definitive evidence that absolves chromic acid. At least one report has suggested that liver damage is a possible consequence of exposure to chromic acid. Other reports have indicated that neither hepatic nor renal Involvement was observed after acute and chronic exposure. In the one report of liver damage, urinary excretion of chromium and the clinical findings of nasal ulceration or mucosal injection and hyperemia suggest significant exposures to chromic acid. The 1928 report by Bloomfield and Blum has served to a great extent as the basis for the previously recommended chromic acid standards of 0.1 mg/cu m. In that paper, the authors concluded that "Continuous daily exposure to concentrations of chromic acid greater than 1 milligram in 10 cubic meters of air is likely to cause definite injury to the nasal tissues of the operators." The lowest concentration to which chromium platers were estimated to have been exposed was 0.12 mg/cu m. Six platers were estimated to have been exposed to that level. One of these had been employed in the plating room approximately one week and two approximately three weeks, yet all six platers suffered slightly (2 of 6) to markedly (4 of 6) Inflamed mucosa. Three of these six, Including the Individual employed only one week, suffered nosebleeds. One plater who had been employed one year was estimated to be exposed to 2.8 mg/cu m at the time of the survey, but suffered no 111 effects, apparently due to personal prophylactic measures. The mucous membranes can be protected, therefore, even against high concentrations of the mist. If the estimates were accurate, the experience of the six platers exposed to 0.12 mg/cu m demonstrates that adverse effects result fairly rapidly from exposures only slightly higher than 0.1 mg/cu m. Thus, the conclusion of the authors that damage Is likely at concentrations above 0.1 mg/cu m seems less an endorsement of that as a safe exposure level, but rather an Indication of the level at which adverse effects can be expected. Zvalfler and Gresh In 1944 reported on over 100 cases observed In an anodizing plant. The majority of these Involved superficial greyish ulceration of the nasal mucosa with engorgement of the vessels and small areas of bleeding in workers not directly associated with the anodizing tanks. Among those working directly ht the tanks, the ulceration involved more of the septum, was deeper, and involved the turbinates and nasal septum as well as the mucosa. The chronic effects reported, lung cancer 32] and liver damage, have not been proved to be a result of exposure to chromic acid, but the possibility of a correlation cannot be rejected. Without better data, it is not possible to establish with confidence what atmospheric concentration will protect against chronic effects if a correlation does exist. Nevertheless, because chronic effects are a possibility, it is recommended that the worker be afforded an additional factor of protection by supplementing the allowable ceiling Of the methods of collection, filtration offers the greatest collection efficiency and ease of collection of breathing zone samples. The AA type of membrane filter has a 0.8 micron pore size and provides a highly retentive matrix for particulates. The use of scrubbing liquids is inconvenient for personal breathing-zone sampling and is thus not recommended. - The iodide-thiosulfate method is subject to Interferences from a wide variety of compounds with its nonspecific iodide reaction and the color definition is subject to a slight error. .The hematoxylin method is suggested only as a check for very small amounts of chromium and is a visual colorimetric method. The use of the colorimetric field analysis technique involving a grab sample and visual analysis must be considered to be only semiquantitatlve, and useful only for that purpose. The colorimetric diphenylcarbazlde method does not react with trivalent chromium but produces a color with only the hexavalent form (present in chromic acid). However, cyanides, organic matter and other reducing agents, iron, copper, and molybdenum at concentrations above 200 ppm and vanadium above 4 ppm, interfere and must be separated or complexed before this method may be expected to provide chromic acid analytical data of an acceptable degree of accuracy precision. The atomic absorption spectrophotometric method, applied directly, determines the total chromium and cannot make the desired distinction between the hexavalent chromium in chromic acid and the trivalent forms of chromium which may be present in the collected sample. Hence, it is necessary to separate the hexavalent from the trivalent chromium compounds by extracting the chelated complex of hexavalent chromium with ammonium pyrrolidine dithiocarbamate into methyl isobutyl ketone and then applying the atomic absorption spectrophotometric method to the extract for a specific determination of hexavalent chromium. Detailed procedures to be followed with emphasis on precautions to be taken in cleaning up and safe disposal of materials leaked or spilled. This includes proper labeling and disposal of containers containing residues, contaminated absorbants, etc. j _ m _ _ l u c i i i hi i i > i 1 1 in " iiifiiif'- » ii u u n n u UTimn c r (1) Section VIII. Special Protection Information. Requirements for personal protective equipment, such as respirators, eye protection, and protective clothing, and ventilation such as local exhaust (at site of product use or application), general, or other special types. (j) Section IX. Special Precautions. Any other general precautionary information such as personal protective equipment for exposure to the thermal decomposition products listed in Section VI, and to particulates formed by abrading a dry coating, such as by a power sanding disc. # (k) The signature of the responsible person filling out the data sheet, his address, and the date on which it is filled out. gas meter can be used. The actual set-up will be the same for these Instruments. Instructions for calibration with the wet-test meter follow. If another calibration device is used, equivalent procedures should be followed. (a) The calibration device used shall be in good working con dition and shall have been calibrated against a spirometer (or other primary standard) upon procurement, after each repair, and at least annually. (b) Calibration curves shall be established for each sampling pump and shall be used in adjusting the pumps prior to field use. # (c) The volumetric flowrate through the sampling system shall be spot checked and the proper adjustments made before and during each study to assure obtaining accurate airflow data. (d) Flowmeter Calibration Test Method (see Figure 1) Allow the layers to separate and add demineralized water until the ketone layer is completely in the neck of the flask. The Cr-APDC complex is stable for at least 36 hours.

Clopidogrel For High Atherothrombotic Risk, Ischemic Stabilization, Management, And Avoidance # Complete Title of Study A Phase III, Multicenter, Multinational, Randomized, Parallel Group, Double-Blind Trial of Clopidogrel Versus Placebo in High-Risk Patients Aged 45 Years and Older, at Risk of Atherothrombotic Events, and Who Are Receiving Background Therapy Including Low-Dose ASA. # Study Acronym (The trial's abbreviation if there is one) CHARISMA # Principal Investigator, Co-investigators, and Collaborating Institutions Study Director: ICD CSD Sanofi-Aventis # Overview of Trial The goal of the study is to compare the efficacy of 75mg once daily clopidogrel with placebo in preventing major cardioavasular events (stroke, MI, cardiovascular death) in high risk patients on a low-dose aspirin therapy (75-162 mg daily) and to compare rates of major and fatal bleeding between the clopidogrel and placebo groups. # Disease State(s) Studied (e.g. acute MI, breast cancer, etc.) Arteriosclerosis # Study Phase (e.g. Phase I,II,III,IV) Study Phases are defined here Phase III # Study Design (e.g. multicenter, randomized, double blind, placebo controlled) Treatment, Randomized, Double Blind (Subject, Investigator), Placebo Control, Parallel Assignment, Safety/Efficacy Study # Study Arms and How They Were Treated (Intervention) (Explanation here) None reported # Primary Pre-Specified Endpoint Combined endpoint of cardiovascular mortality, stroke, acute myocardial infarction. # Secondary Endpoints Severe bleeding # Inclusion Criteria - Be at least 45 years old and comply with at least one of the four categories of inclusion criteria: Combination of atherothrombotic risk factors (2 major or 3 minor or 1 major + 2 minor risk factors among those listed below) - Combination of atherothrombotic risk factors (2 major or 3 minor or 1 major + 2 minor risk factors among those listed below) - Major atherothrombotic risk factors Type I or II diabetes (under drug therapy) Diabetic nephropathy Ankle brachial index (ABI) < 0.9 Asymptomatic carotid stenosis >= 70% At least one carotid plaque as evidenced by intima-media thickness (IMT) - Type I or II diabetes (under drug therapy) - Diabetic nephropathy - Ankle brachial index (ABI) < 0.9 - Asymptomatic carotid stenosis >= 70% - At least one carotid plaque as evidenced by intima-media thickness (IMT) - Minor atherothrombotic risk factors Systolic blood pressure (SBP) >= 150 mmHg, despite appropriate therapy for at least 3 months Primary hypercholesterolemia Current smoking > 15 cigarettes per day Male >= 65 years Female >= 70 years - Systolic blood pressure (SBP) >= 150 mmHg, despite appropriate therapy for at least 3 months - Primary hypercholesterolemia - Current smoking > 15 cigarettes per day - Male >= 65 years - Female >= 70 years - and/or Documented cerebrovascular disease (TIA or IS within 5 years) and/or Documented coronary artery disease (stable angina with documented multivessel coronary disease, previous documented MI, multivessel PCI or CABG within 1 year, multivessel CABG older than 1 year associated with current angina) and/or Documented symptomatic PAD - Documented cerebrovascular disease (TIA or IS within 5 years) and/or - Documented coronary artery disease (stable angina with documented multivessel coronary disease, previous documented MI, multivessel PCI or CABG within 1 year, multivessel CABG older than 1 year associated with current angina) and/or - Documented symptomatic PAD # Exclusion Criteria - Absolute indication for the use of clopidogrel, high-dose aspirin (>162 mg), NSAIDs, or oral anti-thrombotic drugs - Absolute contraindication to the use of clopidogrel or aspirin - Clinical conditions likely to interfere with follow-up leading to inability to complete the trial # Outcome: Primary endpoint (Report both relative risk reduction and absolute risk reduction as well as number needed to treat if available) None reported # Outcome: Secondary endpoint (Report both relative risk reduction and absolute risk reduction as well as number needed to treat if available) None reported # Outcome: Exploratory endpoints (Report both relative risk reduction and absolute risk reduction as well as number needed to treat if available) None reported # Outcome: Safety endpoints (Report both relative risk and absolute risk as well as number needed to harm if available) None reported # Conclusions of the Investigators (Quote the investigators conclusions here) None reported # Commentary, Discussion and Limitations of the Trial (Anyone can add comments) None reported # Slides CHARISMA Slide Sets # Video Commentary June 8, 2007 Dr. Deepak Bhatt and Dr. C. Michael Gibson discuss the CHARISMA trial and the efficacy and safety of clopdiogrel (plavix) # References (How to insert a reference) None reported # External sites for further information (How to insert links) None reported # Detailed information about the trial # Ages 45 years and older # Gender (Indicate whether men, women or both were enrolled) Both # Accepts Healthy Volunteers (Answer yes or no) No # Enrollment Period (Study start and end date) Start Date: October 2002 Completion Date: August 2005 # Recruitment Status (explanation) Completed # Enrollment (Total number of patients enrolled) # Study Sponsor (e.g. Investigator initiated or company name) Sanofi-Aventis # Source of Data (Where is this data on this page coming from: publication, principal investigator, or co-investigator) Sanofi-Aventis The content of the clinical trial wiki consists of fields that have been suggested by the World Health Organization and wwww.clinicaltrials.gov.

Stereoblindness Stereoblindness (also stereo blindness) is the inability to see in 3D using stereo vision, resulting in inability to perceive stereoscopic depth. Individuals with only one eye always have this condition; the condition also results when two eyes do not work in proper concert. It has been asserted that the Dutch painter Rembrandt may have been stereoblind, which would have aided him in flattening what he saw for the production of 2D works .

Doxazosin (patient information) # Why this medication is prescribed? Doxazosin (Cardura, Cardura XL) is used in men to treat the symptoms of an enlarged prostate (benign prostatic hyperplasia or BPH), which include difficulty urinating (hesitation, dribbling, weak stream, and incomplete bladder emptying), painful urination, and urinary frequency and urgency. Doxazosin (Cardura) is also used alone or in combination with other medications to treat high blood pressure. Doxazosin is in a class of medications called alpha-blockers. It relieves the symptoms of BPH by relaxing the muscles of the bladder and prostate. It lowers blood pressure by relaxing the blood vessels so that blood can flow more easily through the body. # How this medication should be used? Doxazosin comes as a tablet and an extended-release tablet to take by mouth. The doxazosin tablet is usually taken with or without food once a day in the morning or in the evening. The doxazosin extended-release tablet is usually taken once a day with breakfast. To help you remember to take doxazosin, take it around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take doxazosin exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor. Swallow the extended-release tablets whole; do not split, chew, or crush them. Your doctor will start you on a low dose of doxazosin and gradually increase your dose, not more than once every 1 to 2 weeks. If you stop taking doxazosin for a few days or longer, call your doctor. Your doctor will have to start you again on the lowest dose of doxazosin and gradually increase your dose. Doxazosin controls high blood pressure and the symptoms of BPH but does not cure them. It may take a few weeks before you feel the full benefit of doxazosin. Continue to take doxazosin even if you feel well. Do not stop taking doxazosin without talking to your doctor. # Other uses for this medicine This medication may be prescribed for other uses; ask your doctor or pharmacist for more information. # Special Precautions Before taking doxazosin: - tell your doctor and pharmacist if you are allergic to doxazosin, prazosin (Minipress), terazosin (Hytrin), or any other medications. - tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: antihistamines; clarithromycin (Biaxin, in Prevpac); ipratropium (Atrovent); itraconazole (Sporanox); ketoconazole (Nizoral); medications for erectile dysfunction (ED) such as sildenafil (Viagra), tadalafil (Cialis), or vardenafil (Levitra); medications for high blood pressure; medications for HIV/AIDS including atazanavir (Reyataz), indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir, in Kaletra), or saquinavir (Fortovase, Invirase); medications for irritable bowel disease, motion sickness, Parkinson's disease, ulcers, or urinary problems; nefazodone; telithromycin (Ketek); and voriconazole(Vfend). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. - tell your doctor if you have angina (chest pain); low blood pressure; or if you have or have ever had prostate canceror liver disease. If you are taking the extended-release tablet, tell you doctor if you have constipation, short bowel syndrome (a condition where more than half of the small intestine has been removed by surgery or damaged by disease), or narrowing or a blockage of the intestines. - tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking doxazosin, call your doctor. - if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking doxazosin. If you need to have eye surgery at any time during or after your treatment, be sure to tell your doctor that you are taking or have taken doxazosin. - you should know that doxazosin may make you drowsy or dizzy. Do not drive a car, operate machinery, or perform dangerous tasks for 24 hours after the first time you take doxazosin or after your dose is increased. - you should know that doxazosin may cause dizziness, lightheadedness, and fainting when you get up too quickly from a lying position. This is more common when you first start taking doxazosin, when your dose is increased, or if your treatment has been stopped for more than a few days. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up. If you experience these symptoms, sit or lie down. If these symptoms do not improve, call your doctor. # Special dietary instructions Follow your doctor's directions for your meals, including advice for a reduced salt (sodium) diet. # What to do if you forget a dose? Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one. Check with your doctor if you have missed two or more doses. # Side Effects ## Minor Side Effects Doxazosin may cause side effects. Tell your doctor if any of these symptoms or those listed in the SPECIAL PRECAUTIONS section are severe or do not go away: - headache - tiredness - swelling of the hands, feet, ankles, or lower legs - shortness of breath - weight gain - muscle or joint pain or weakness - abnormal vision - runny nose - decreased sexual ability ## Severe Side Effects Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately: - rapid, pounding, or irregular heartbeat - chest pain - shortness of breath - hives - painful erection of the penis that lasts for hours Doxazosin may cause other side effects. Call your doctor if you have any unusual problems while taking this medication. # Storage conditions needed for this medication Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication. # In case of emergency/overdose In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911. Symptoms of overdose may include: - drowsiness - dizziness - lightheadedness - fainting - seizure # Other information If you are taking doxazosin extended-release tablets, you may notice something that looks like a tablet in your stool. This is just the empty tablet shell, and this does not mean that you did not get your complete dose of medication. Keep all appointments with your doctor. If you are taking doxazosin to control high blood pressure, your blood pressure should be checked regularly to determine your response to doxazosin. Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription. # Brand names - Cardura® - Cardura ® XL

Fluorescence resonance energy transfer Fluorescence resonance energy transfer (FRET) describes an energy transfer mechanism between two chromophores. A donor chromophore in its excited state can transfer energy by a nonradiative, long-range dipole-dipole coupling mechanism to an acceptor chromophore in close proximity (typically <10nm). This energy transfer mechanism is termed "Förster resonance energy transfer" (FRET), named after the German scientist Theodor Förster. When both molecules are fluorescent, the term "fluorescence resonance energy transfer" is often used, although the energy is not actually transferred by fluorescence.,. In order to avoid an erroneous interpretation of the phenomenon that, even when occurring between two fluorescent molecules, is always a nonradiative transfer of energy, the name "Förster resonance energy transfer" may be preferred to "Fluorescence resonance energy transfer". # Theoretical basis The FRET efficiency (E) is the quantum yield of the energy transfer transition, i.e. the fraction of energy tranfer event occurring per donor excitation event: where k_{ET} is the rate of energy transfer, k_{f} the radiative decay rate and the k_{i} are the rate constants of any other de-excitation pathway. The FRET efficiency depends on many parameters that can be grouped as follows: - The distance between the donor and the acceptor - The spectral overlap of the donor emission spectrum and the acceptor absorption spectrum. - The relative orientation of the donor emission dipole moment and the acceptor absorption dipole moment. E depends on the donor-to-acceptor separation distance r with an inverse 6th power law due to the dipole-dipole coupling mechanism: with R_0 being the Förster distance of this pair of donor and acceptor at which the FRET efficiency is 50%. The Förster distance depends on the overlap integral of the donor emission spectrum with the acceptor absorption spectrum and their mutual molecular orientation as expressed by the following equation: where \kappa^2 is the dipole orientation factor, n is the refractive index of the medium, Q_0 is the fluorescence quantum yield of the donor in the absence of the acceptor, and J is the spectral overlap integral calculated as where f_{\rm D} is the normalized donor emission spectrum, and \epsilon_{\rm A} is the acceptor molar extinction coefficient. κ2 =2/3 is often assumed. This value is obtained when both dyes are freely rotating and can be considered to be isotropically oriented during the excited state lifetime. If either dye is fixed or not free to rotate, then κ2 =2/3 will not be a valid assumption. In most cases, however, even modest reorientation of the dyes results in enough orientational averaging that κ2 = 2/3 does not result in a large error in the estimated energy transfer distance due to the sixth power dependence of R0 on κ2. Even when κ2 is quite different from 2/3 the error can be associated with a shift in R0 and thus determinations of changes in relative distance for a particular system are still valid. Fluorescent proteins do not reorient on a timescale that is faster than their fluorescence lifetime. In this case 0 ≤ κ2 ≤ 4. The FRET efficiency relates to the quantum yield and the fluorescence lifetime of the donor molecule as follows: where \tau'_{\rm D} and \tau_{\rm D} are the donor fluorescence lifetimes in the presence and absence of an acceptor, respectively, or as where F'_{\rm D} and F_{\rm D} are the donor fluorescence intensities with and without an acceptor, respectively. # Methods In fluorescence microscopy, fluorescence confocal laser scanning microscopy, as well as in molecular biology, FRET is a useful tool to quantify molecular dynamics in biophysics and biochemistry, such as protein-protein interactions, protein-DNA interactions, and protein conformational changes. For monitoring the complex formation between two molecules, one of them is labeled with a donor and the other with an acceptor, and these fluorophore-labeled molecules are mixed. When they are dissociated, the donor emission is detected upon the donor excitation. On the other hand, when the donor and acceptor are in proximity (1-10 nm) due to the interaction of the two molecules, the acceptor emission is predominantly observed because of the intermolecular FRET from the donor to the acceptor. For monitoring protein conformational changes, the target protein is labeled with a donor and an acceptor at two loci. When a twist or bend of the protein brings the change in the distance or relative orientation of the donor and acceptor, FRET change is observed. If a molecular interaction or a protein conformational change is dependent on ligand binding, this FRET technique is applicable to fluorescent indicators for the ligand detection. FRET studies are scalable: the extent of energy transfer is often quantified from the milliliter scale of cuvette-based experiments to the femtoliter scale of microscopy-based experiments. This quantification can be based directly (sensitized emission method) on detecting two emission channels under two different excitation conditions (primarily donor and primarily acceptor). However, for robustness reasons, FRET quantification is most often based on measuring changes in fluorescence intensity or fluorescence lifetime upon changing the experimental conditions (e.g. a microscope image of donor emission is taken with the acceptor being present. The acceptor is then bleached, such that it is incapable of accepting energy transfer and another donor emission image is acquired. A pixel-based quantification using the second equation in the theory section above is then possible.) An alternative way of temporarily deactivating the acceptor is based on its fluorescence saturation. Exploiting polarisation characteristics of light, a FRET quantification is also possible with only a single camera exposure. ## CFP-YFP pairs The most popular FRET pair for biological use is a cyan fluorescent protein (CFP)-yellow fluorescent protein (YFP) pair. Both are color variants of green fluorescent protein (GFP). While labeling with organic fluorescent dyes requires troublesome processes of purification, chemical modification, and intracellular injection of a host protein, GFP variants can be easily attached to a host protein by genetic engineering. By virtue of GFP variants, the use of FRET techniques for biological research is becoming more and more popular. ## BRET A limitation of FRET is the requirement for external illumination to initiate the fluorescence transfer, which can lead to background noise in the results from direct excitation of the acceptor or to photobleaching. To avoid this drawback, Bioluminescence Resonance Energy Transfer (or BRET) has been developed. This technique uses a bioluminescent luciferase (typically the luciferase from Renilla reniformis) rather than CFP to produce an initial photon emission compatible with YFP. FRET and BRET are also the common tools in the study of biochemical reaction kinetics and molecular motors. ## Other methods A different, but related, mechanism is Dexter Electron Transfer. An alternative method to detecting protein-protein proximity is BiFC where two halves of a YFP are fused to a protein (Hu, Kerppola et al. 2002). When these two halves meet they form a fluorophore after about 60 s - 1 hr. # Applications FRET has been applied in an experimental method for the detection of phosgene. In it, phosgene or rather triphosgene as a safe substitute serves as a linker between an acceptor and a donor coumarine (forming urea groups). The presence of phosgene is detected at 5x10-5M with a typical FRET emission at 464 nm.