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Ozon luchtzuiveringsinstallaties kunnen permanente longschade veroorzaken
Verkopers van ozon producerende apparaten gebruiken vaak fantasievolle voorwaarden om te beschrijven van ozon. Het wordt aangeduid in termen als "geactiveerde zuurstof" replica hermes handbags of "zuivere lucht", die doen vermoeden dat ozon niets anders dan een gezond soort zuurstof is. Ozon is echter een giftige gassen die enorm verschillende chemische en toxicologische eigenschappen vergeleken met zuurstof heeft.Ozon is een molecule bestaat uit drie atomen van zuurstof, in tegenstelling tot de zuurstof we normaal adem, die heeft twee. De O2 molecule is stabiel en nonreactive, terwijl de O3 molecule instabiel is, de neiging te distantiren en produceren een O2 molecuul en n enkele geoniseerde zuurstof atoom. Dit enkel atoom fungeert als een "vrije radicle", dat wil zeggen, het reageert met andere nabijgelegen stoffen en hun chemische samenstelling verandert. Het is dit vermogen te combineren met andere stoffen, die de basis van fabrikanten beweert vormt dat het bindt van organische deeltjes in de lucht en ze uit omloop genomen verwijdert.Jammer genoeg, dezelfde chemische eigenschappen waarmee ozon te reageren met organisch materiaal in de omgeving ook geeft het de mogelijkheid om te reageren met soortgelijke organisch materiaal in het lichaam, met mogelijk schadelijke gezondheidsgevolgen. Bij inademing, ozon kan schade aan de longen, en het wordt beschouwd als een ongewenste stof dat is een onderdeel van smog.Inademing van ozon op zelfs lage bedragen kan leiden tot ademhalingsproblemen en irritatie van de keel. Bovendien, ozon chronische respiratoire aandoeningen zoals astma verergert en belemmert de natuurlijke vermogen van het lichaam tegen infecties van de luchtwegen.Een algemeen aanvaarde theorie van veroudering stelt dat de cellen van het menselijk lichaam leeftijd zowel als gevolg van genetische factoren (verlies van cel telomeren) en oxidatieve schade door vrije radicalen. Mensen worden aangemoedigd om te eten van een dieet hoog in antioxidanten, en velen nemen antioxidant supplementen, juist om te voorkomen dat de aard van de schade veroorzaakt door reactieve stoffen zoals ozon.De meeste mensen herstellen van acute blootstelling aan ozon, maar langdurige blootstelling kan volgens een studie van 1996 EPA, permanente longschade veroorzaken. De EPA beschouwt ozon als een luchtvervuiler en normen voor de luchtkwaliteit zodat lokale ambtenaren waarschuwen het publiek wanneer ozonniveaus in stedelijke gebieden buitensporige zijn heeft geformuleerd. Wanneer ozon (en andere luchtverontreinigende stoffen) hoog zijn, astmapatinten en patinten met chronische longziekte worden aangemoedigd om te verblijven binnen en gezonde mensen worden verteld om zich te onthouden van zware buiten oefening die hun ademhalingstarief in de giftige lucht oproept. Aangezien mensen worden geadviseerd om te voorkomen dat ozon in de outdoor omgeving, is het moeilijk te begrijpen waarom iemand zou kopen, een apparaat om doelbewust produceren binnen hun eigen huizen.De FDA vereist ozon uitvoer binnen medische apparatuur om minder dan 0,05 ppm. De Occupational Safety and Health Administration (OSHA) vereist dat blootstelling van werknemers aan ozon niet meer bedragen dan een gemiddelde concentratie van meer dan 0,10 ppm voor 8 uur. Het nationale Instituut voor veiligheid en gezondheid op het werk (NIOSH) beveelt een bovengrens van 0,10 ppm die niet zelfs kort mag worden overschreden. EPA's nationale Ambient Air kwaliteitsnorm voor ozon is een maximaal 8 uur gemiddelde buiten concentratie van 0,08 ppm.De EPA bedacht de uitdrukking "goede up hoge slecht in de buurt" om te differentiren tussen ozon in de atmosfeer boven en onderlichaam. Stratosferische ozon in de bovenste atmosfeer ongeveer 10 tot 50km (32.000 tot 164.000 voet) boven aardoppervlak helpt uitfilteren van schadelijke ultraviolette zonnestraling. Deze ozonlaag is gedecimeerd door CFC verbindingen die worden gebruikt in koelkasten en koelvloeistof systemen. Dit is valse reclame voor verschillende redenen.Ten eerste, het duurt maanden tot en met jaar voor ozon te reageren met veel van de chemische stoffen die gewoonlijk worden aangetroffen in binnenlucht (Boeniger, 1995); dus voor alle praktische doeleinden, dit is nutteloos. Ook, Ozongeneratoren verwijdert geen koolmonoxide (Salls, 1927; Shaughnessy et al., 1994) of formaldehyde (Esswein en Boeniger, 1994).Ten tweede, in veel gevallen waar de reactie tussen de verontreinigende stoffen en ozon gemakkelijk treedt op, de bijproducten zijn zo schadelijk of irritant als de oorspronkelijke verontreinigende stoffen (Weschler et al., 1992a, 1992b, 1996; Zhang en Lioy, 1994).Bijvoorbeeld, een laboratorium experiment werd uitgevoerd die ozon gemengd met chemische stoffen uit nieuw tapijt. Ozon veel van de chemische stoffen, met inbegrip van die produceren kan "nieuw tapijt" verminderen geur. Echter, de reactie geproduceerd een verscheidenheid replica hermes bag van aldehyden, en de totale concentratie van organische chemische stoffen in de lucht eigenlijk verhoogde (Weschler, et. al., 1992b). Niveaus hinderlijke mierenzuur ook stijgen (Zhang en Lioy, 1994).Sommige van de bijproducten van ozon reactie zijn zelf reactieve en ga naar producten verder irriterend en bijtende bijproducten (Weschler en schilden, 1996, 1997a, 1997b). Ozon produceren apparaten omzetten een binnenmilieu in een maatkolf van ziedende chemische.Ten derde, ozon door zelf wordt niet verwijderd lucht zwevende deeltjes zoals stuifmeel en housedust. Echter, sommige Ozongeneratoren zijn vervaardigd met een "ion generator" of "ionisator" in dezelfde eenheid te verspreiden negatief (en/of positief) geladen ionen in de lucht. Deze ionen hechten aan deeltjes in de lucht geven hen een negatieve (of positieve) kosten, zodat de deeltjes aan nabijgelegen oppervlakken zoals muren of meubilair hechten kunnen, maken een ongewenste groezelige laag; of aan elkaar koppelen en regelen uit de lucht. In recente experimenten, ionizers bewezen ineffectief in het verwijderen van stof, tabaksrook, pollen of schimmelsporen in vergelijking met hoge efficintie deeltjesfilters of elektrostatische precipitators. (Shaughnessy et al., 1994; Pierce, et al., 1996).Zelfs bij concentraties die aanzienlijk hoger zijn dan de volksgezondheid normen, is ozon niet effectief bij het reinigen van de lucht. En helaas, er is bewijs om te suggereren dat in bepaalde omstandigheden ozon genereren apparaten draaglijk uitvoer grenzen overschrijden. Als gevolg van de verschillende merken en modellen van deze machines, alsmede van de omvang van de andere kamer waar ze uiteindelijk worden gebruikt, kunnen er grote variatie in de uiteindelijke concentratie van ozon in de lucht.In een studie van Shaughnessy en Oatman (1991), een grote ozon generator aanbevolen door de fabrikant voor ruimten "tot 3.000 vierkante meter," werd geplaatst in een 350 vierkante voet kamer en run op een hoge instelling. De ozon in de kamer bereikt snel gevaarlijke niveaus van 0,50 naar 0,80 ppm, 5 10 keer hoger dan de volksgezondheid grenzen.In een studie van de EPA 1995, werden verschillende verschillende Ozongeneratoren getest in een huiselijke omgeving, in kamers van verschillende grootte, met deuren afwisselend geopend en gesloten, en met de centrale ventilator voor systeem afwisselend draaide in en uitschakelen. De resultaten toonden aan dat sommige Ozongeneratoren, wanneer replica birkin handbags uitgevoerd bij maximale instellingen in een gesloten kamer, vaak gevaarlijke concentraties van 0.20 0,30 ppm geproduceerd. Wanneer de eenheden werden uitgevoerd bij de kleinere instellingen met interieur deuren geopend, concentraties in het algemeen binnen de volksgezondheid how much is a hermes bag normen gebleven.Als gevolg van deze brede variatie van de productie en concentratie is het onmogelijk voor de consument om te weten hoeveel ozon is eigenlijk in de lucht die zij inademen; in vele normale omstandigheden, kunnen Ozongeneratoren produceren giftige niveaus. Ten minste n fabrikant is de verkoop van machines uitgerust met ozon sensoren die de machine zet in en uitschakelen in reactie op de ozonconcentraties, teneinde de niveaus van dit geheel ongewenste gas binnen een 'veilige' bereik. Het doet me denken aan die afzichtelijk boxy, oude ouderwetse auto's, waar niet meer dan een kramp, en een viool werd besteed aan het esthetisch design van het item of in dit geval, de koelkast. Ik heb mijn beide koelkasten overtuigd dat ze in feite cork borden zijn gedekt van kop tot teen met postkaarten verzonden uit het buitenland, gewoon te laten voelen als ze nog steeds in de running voor keuken toestel met de meeste karakter.De uitvinding van tapijten gemaakt de onvermijdelijke uitvinding van tapijt reinigen van machines. 1860 gemarkeerd het jaar het eerste handheld tapijt schoner is ontworpen en getest, in Chicago, IL. Slechts 40 jaar gingen voorbij voordat Cecil Booth de eerste macht uitgevonden gexploiteerd stofzuiger in 1900.
Verkopers van ozon producerende apparaten gebruiken vaak fantasievolle voorwaarden om te beschrijven van ozon. Het wordt aangeduid in termen als "geactiveerde zuurstof" replica hermes handbags of "zuivere lucht", die doen vermoeden dat ozon niets anders dan een gezond soort zuurstof is. Ozon is echter een giftige gassen die enorm verschillende chemische en toxicologische eigenschappen vergeleken met zuurstof heeft.Ozon is een molecule bestaat uit drie atomen van zuurstof, in tegenstelling tot de zuurstof we normaal adem, die heeft twee. De O2 molecule is stabiel en nonreactive, terwijl de O3 molecule instabiel is, de neiging te distantiren en produceren een O2 molecuul en n enkele geoniseerde zuurstof atoom. Dit enkel atoom fungeert als een "vrije radicle", dat wil zeggen, het reageert met andere nabijgelegen stoffen en hun chemische samenstelling verandert. Het is dit vermogen te combineren met andere stoffen, die de basis van fabrikanten beweert vormt dat het bindt van organische deeltjes in de lucht en ze uit omloop genomen verwijdert.Jammer genoeg, dezelfde chemische eigenschappen waarmee ozon te reageren met organisch materiaal in de omgeving ook geeft het de mogelijkheid om te reageren met soortgelijke organisch materiaal in het lichaam, met mogelijk schadelijke gezondheidsgevolgen. Bij inademing, ozon kan schade aan de longen, en het wordt beschouwd als een ongewenste stof dat is een onderdeel van smog.Inademing van ozon op zelfs lage bedragen kan leiden tot ademhalingsproblemen en irritatie van de keel. Bovendien, ozon chronische respiratoire aandoeningen zoals astma verergert en belemmert de natuurlijke vermogen van het lichaam tegen infecties van de luchtwegen.Een algemeen aanvaarde theorie van veroudering stelt dat de cellen van het menselijk lichaam leeftijd zowel als gevolg van genetische factoren (verlies van cel telomeren) en oxidatieve schade door vrije radicalen. Mensen worden aangemoedigd om te eten van een dieet hoog in antioxidanten, en velen nemen antioxidant supplementen, juist om te voorkomen dat de aard van de schade veroorzaakt door reactieve stoffen zoals ozon.De meeste mensen herstellen van acute blootstelling aan ozon, maar langdurige blootstelling kan volgens een studie van 1996 EPA, permanente longschade veroorzaken. De EPA beschouwt ozon als een luchtvervuiler en normen voor de luchtkwaliteit zodat lokale ambtenaren waarschuwen het publiek wanneer ozonniveaus in stedelijke gebieden buitensporige zijn heeft geformuleerd. Wanneer ozon (en andere luchtverontreinigende stoffen) hoog zijn, astmapatinten en patinten met chronische longziekte worden aangemoedigd om te verblijven binnen en gezonde mensen worden verteld om zich te onthouden van zware buiten oefening die hun ademhalingstarief in de giftige lucht oproept. Aangezien mensen worden geadviseerd om te voorkomen dat ozon in de outdoor omgeving, is het moeilijk te begrijpen waarom iemand zou kopen, een apparaat om doelbewust produceren binnen hun eigen huizen.De FDA vereist ozon uitvoer binnen medische apparatuur om minder dan 0,05 ppm. De Occupational Safety and Health Administration (OSHA) vereist dat blootstelling van werknemers aan ozon niet meer bedragen dan een gemiddelde concentratie van meer dan 0,10 ppm voor 8 uur. Het nationale Instituut voor veiligheid en gezondheid op het werk (NIOSH) beveelt een bovengrens van 0,10 ppm die niet zelfs kort mag worden overschreden. EPA's nationale Ambient Air kwaliteitsnorm voor ozon is een maximaal 8 uur gemiddelde buiten concentratie van 0,08 ppm.De EPA bedacht de uitdrukking "goede up hoge slecht in de buurt" om te differentiren tussen ozon in de atmosfeer boven en onderlichaam. Stratosferische ozon in de bovenste atmosfeer ongeveer 10 tot 50km (32.000 tot 164.000 voet) boven aardoppervlak helpt uitfilteren van schadelijke ultraviolette zonnestraling. Deze ozonlaag is gedecimeerd door CFC verbindingen die worden gebruikt in koelkasten en koelvloeistof systemen. Dit is valse reclame voor verschillende redenen.Ten eerste, het duurt maanden tot en met jaar voor ozon te reageren met veel van de chemische stoffen die gewoonlijk worden aangetroffen in binnenlucht (Boeniger, 1995); dus voor alle praktische doeleinden, dit is nutteloos. Ook, Ozongeneratoren verwijdert geen koolmonoxide (Salls, 1927; Shaughnessy et al., 1994) of formaldehyde (Esswein en Boeniger, 1994).Ten tweede, in veel gevallen waar de reactie tussen de verontreinigende stoffen en ozon gemakkelijk treedt op, de bijproducten zijn zo schadelijk of irritant als de oorspronkelijke verontreinigende stoffen (Weschler et al., 1992a, 1992b, 1996; Zhang en Lioy, 1994).Bijvoorbeeld, een laboratorium experiment werd uitgevoerd die ozon gemengd met chemische stoffen uit nieuw tapijt. Ozon veel van de chemische stoffen, met inbegrip van die produceren kan "nieuw tapijt" verminderen geur. Echter, de reactie geproduceerd een verscheidenheid replica hermes bag van aldehyden, en de totale concentratie van organische chemische stoffen in de lucht eigenlijk verhoogde (Weschler, et. al., 1992b). Niveaus hinderlijke mierenzuur ook stijgen (Zhang en Lioy, 1994).Sommige van de bijproducten van ozon reactie zijn zelf reactieve en ga naar producten verder irriterend en bijtende bijproducten (Weschler en schilden, 1996, 1997a, 1997b). Ozon produceren apparaten omzetten een binnenmilieu in een maatkolf van ziedende chemische.Ten derde, ozon door zelf wordt niet verwijderd lucht zwevende deeltjes zoals stuifmeel en housedust. Echter, sommige Ozongeneratoren zijn vervaardigd met een "ion generator" of "ionisator" in dezelfde eenheid te verspreiden negatief (en/of positief) geladen ionen in de lucht. Deze ionen hechten aan deeltjes in de lucht geven hen een negatieve (of positieve) kosten, zodat de deeltjes aan nabijgelegen oppervlakken zoals muren of meubilair hechten kunnen, maken een ongewenste groezelige laag; of aan elkaar koppelen en regelen uit de lucht. In recente experimenten, ionizers bewezen ineffectief in het verwijderen van stof, tabaksrook, pollen of schimmelsporen in vergelijking met hoge efficintie deeltjesfilters of elektrostatische precipitators. (Shaughnessy et al., 1994; Pierce, et al., 1996).Zelfs bij concentraties die aanzienlijk hoger zijn dan de volksgezondheid normen, is ozon niet effectief bij het reinigen van de lucht. En helaas, er is bewijs om te suggereren dat in bepaalde omstandigheden ozon genereren apparaten draaglijk uitvoer grenzen overschrijden. Als gevolg van de verschillende merken en modellen van deze machines, alsmede van de omvang van de andere kamer waar ze uiteindelijk worden gebruikt, kunnen er grote variatie in de uiteindelijke concentratie van ozon in de lucht.In een studie van Shaughnessy en Oatman (1991), een grote ozon generator aanbevolen door de fabrikant voor ruimten "tot 3.000 vierkante meter," werd geplaatst in een 350 vierkante voet kamer en run op een hoge instelling. De ozon in de kamer bereikt snel gevaarlijke niveaus van 0,50 naar 0,80 ppm, 5 10 keer hoger dan de volksgezondheid grenzen.In een studie van de EPA 1995, werden verschillende verschillende Ozongeneratoren getest in een huiselijke omgeving, in kamers van verschillende grootte, met deuren afwisselend geopend en gesloten, en met de centrale ventilator voor systeem afwisselend draaide in en uitschakelen. De resultaten toonden aan dat sommige Ozongeneratoren, wanneer replica birkin handbags uitgevoerd bij maximale instellingen in een gesloten kamer, vaak gevaarlijke concentraties van 0.20 0,30 ppm geproduceerd. Wanneer de eenheden werden uitgevoerd bij de kleinere instellingen met interieur deuren geopend, concentraties in het algemeen binnen de volksgezondheid how much is a hermes bag normen gebleven.Als gevolg van deze brede variatie van de productie en concentratie is het onmogelijk voor de consument om te weten hoeveel ozon is eigenlijk in de lucht die zij inademen; in vele normale omstandigheden, kunnen Ozongeneratoren produceren giftige niveaus. Ten minste n fabrikant is de verkoop van machines uitgerust met ozon sensoren die de machine zet in en uitschakelen in reactie op de ozonconcentraties, teneinde de niveaus van dit geheel ongewenste gas binnen een 'veilige' bereik. Het doet me denken aan die afzichtelijk boxy, oude ouderwetse auto's, waar niet meer dan een kramp, en een viool werd besteed aan het esthetisch design van het item of in dit geval, de koelkast. Ik heb mijn beide koelkasten overtuigd dat ze in feite cork borden zijn gedekt van kop tot teen met postkaarten verzonden uit het buitenland, gewoon te laten voelen als ze nog steeds in de running voor keuken toestel met de meeste karakter.De uitvinding van tapijten gemaakt de onvermijdelijke uitvinding van tapijt reinigen van machines. 1860 gemarkeerd het jaar het eerste handheld tapijt schoner is ontworpen en getest, in Chicago, IL. Slechts 40 jaar gingen voorbij voordat Cecil Booth de eerste macht uitgevonden gexploiteerd stofzuiger in 1900.
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Orangutan Females Steal Hermes Kelly bag replica Food to Test Potential Mates
When males reacted violently or took fake hermes kelly bagd the food back, the females fake hermes leather handbags screamed and tended to end the interactions much sooner than when the male tolerated the stealing.
Evolutionarily, the behavior makes sense, experts say, since relationships with aggressive males can be extremely damaging for females.
Males who are aggressive to other males may attract females.
"She could endure injuries, from bruises to broken bones, replica hermes birkin handbags if his attacks were to knock her out of a tree," van Noordwijk said.
The researchers did not see the females give immediate sexual favors in return for the males tolerating the food stealing.
But, van Noordwijk said, "we think the stealing allows females to test males for their tendency to be aggressive toward them so they can determine whether they are worth further associating with."
When males reacted violently or took fake hermes kelly bagd the food back, the females fake hermes leather handbags screamed and tended to end the interactions much sooner than when the male tolerated the stealing.
Evolutionarily, the behavior makes sense, experts say, since relationships with aggressive males can be extremely damaging for females.
Males who are aggressive to other males may attract females.
"She could endure injuries, from bruises to broken bones, replica hermes birkin handbags if his attacks were to knock her out of a tree," van Noordwijk said.
The researchers did not see the females give immediate sexual favors in return for the males tolerating the food stealing.
But, van Noordwijk said, "we think the stealing allows females to test males for their tendency to be aggressive toward them so they can determine whether they are worth further associating with."
Outcome after resuscitation beyond 30 minutes in drowned children with cardiac arrest and hypothermia
Participants Children aged up to 16 with cardiac arrest and hypothermia after drowning, who presented at emergency departments and/or were admitted to intensive care.
Main outcome measure Survival and neurological outcome one year after the drowning incident. Poor outcome was defined as death or survival in a vegetative state or with severe neurological disability (paediatric cerebral performance category (PCPC) 4).
Results From 1993 to 2012, 160 children presented with cardiac arrest and hypothermia after drowning. In 98 (61%) of these children resuscitation was performed for more than 30 minutes (98/160, median duration 60 minutes), of whom 87 (89%) died (95% confidence interval 83% to 95%; 87/98). Eleven of the 98 children survived (11%, 5% to 17%), but all had a PCPC score 4. In the 62 (39%) children who did not require prolonged resuscitation, 17 (27%, 16% to 38%) survived with a PCPC score 3 after one year: 10 (6%) had a good neurological outcome (score 1), five (3%) had mild neurological disability (score 2), and two (1%) had moderate neurological disability (score 3). From the original 160 children, only 44 were alive at one year with any outcome.
Conclusions Drowned children in whom return of spontaneous circulation is not achieved within 30 minutes of advanced life support have an extremely poor outcome. Good neurological outcome is more likely when spontaneous circulation returns within 30 minutes of advanced life support, especially when the drowning incident occurs in winter. These findings question the therapeutic value of resuscitation beyond 30 minutes in drowned children with cardiac arrest and hypothermia. Many houses are built near to ponds, ditches, or canals. A temperate maritime climate prevails, with mean air temperatures of 3.5C in winter, 9.5C in spring, 10.6C in autumn, and 17.0C in summer and water temperatures ranging from 0 8C in winter, 6 18C in spring and autumn, and 15 28C in summer.19 20
The Dutch emergency medical service has a legally enforced arrival time of less than 15 minutes for medical emergencies.21 All ambulance teams consist of a nurse trained in paediatric basic and advanced life support and allowed to perform intubation and administration of adrenaline (epinephrine) in children and a driver trained in paediatric basic life support. In cases of a cardiac arrest, a second emergency medical team is always called on, and, since 1999, this second team is often the helicopter emergency medical service with a physician on board.
Prehospital treatment is provided by emergency medical service nurses according to Dutch national ambulance protocols. These protocols are in accordance with the guidelines of the European Resuscitation Council. The national ambulance protocols how much is a hermes handbag instruct that all children with cardiac arrest and hypothermia should be transported, under continuous cardiopulmonary resuscitation, to a hospital with facilities for extracorporeal life support. The physicians of the helicopter emergency medical service and the emergency department treat according to the replica hermes birkin handbags guidelines of the Dutch Resuscitation Council and the European Resuscitation Council. All children with return of spontaneous circulation after prolonged resuscitation, whether primarily presented at the emergency department of a general hospital or a university medical centre, are transferred to a paediatric intensive care unit in one of the eight university medical centres.
PatientsWe retrospectively identified eligible patients by using the ICD 9 (international classification of diseases, ninth edition) code for drowning (994.1). For those aged 16 and under, their demographical and clinical data were entered in the database when they were admitted at the emergency department, the general paediatric ward, or the paediatric intensive care unit of one of the eight university medical centres from 1 January 1993 to 1 January 2012. Children who presented at the emergency department of a general hospital and transferred to the paediatric intensive care unit were included in this database.
Inclusion and exclusion criteriaWe included children with cardiac arrest after drowning outside (excluding heated outdoor swimming pools) and an initial core body temperature below 34C. Drowning outside was an inclusion criterion so hermes replica we could use season as a proxy for water temperature. As concurrent traumatic injuries could possibly influence outcome, we excluded children who drowned in a traffic or boating incident.
VariablesThe data collection was based on the Utstein style variables for uniform reporting of data from drowning.22 Data collected at the arrival of the emergency medical service included initial cardiac arrest rhythm, the use of bag and mask ventilation, intubation, duration of chest compressions, and number of doses of adrenaline and attempts at defibrillation. Data collected at the emergency department included initial core body temperature, score on Glasgow coma scale, the use of bag and mask ventilation, intubation, duration of chest compressions, number of doses of adrenaline, use of extracorporeal life support for cardiac arrest, and return of spontaneous circulation or death. Data collected at the paediatric intensive care unit included death or discharge, the cause of death, and, if applicable, the withdrawal of life sustaining treatment. Final disposition was dead or alive at one year after the drowning incident, and, if alive, the neurological status according to the paediatric cerebral performance category score (PCPC).23
DefinitionsThe minimum and maximum durations of submersion were taken from the medical records and were based on estimations by the caretaker(s) of the child at the time of incident. Cardiac arrest was defined as the necessity for chest compressions on arrival of the emergency medical service or and/or helicopter emergency medical service. The start point of the resuscitation time was marked by the initiation of chest compressions by the emergency services and the total duration of resuscitation included prehospital and in hospital advanced life support but excluded bystander cardiopulmonary resuscitation. Prolonged resuscitation was defined as more than 30 minutes of total resuscitation. This cut off was chosen because the mean attempted resuscitation time in many studies concerning resuscitation in children with out of hospital cardiac arrest averaged 30 minutes.24 We defined spring as the period between 1 March and 31 May, summer between 1 June and 31 August, autumn between 1 September and 30 November, and winter between 1 December and 29 February.
Initial cardiac arrest rhythm was the first rhythm visible after connection of the patient to the electrocardiograph of the emergency medical services. Initial temperature was defined as the first body temperature measured within one hour after arrival at the emergency department and concerned measurements of rectal or oesophageal temperature with a low reading thermometer. The initial blood gas analysis was measured within two hours after arrival at the emergency department. The term extracorporeal life support was used to indicate both extracorporeal circulation and extracorporeal membrane oxygenation. In the paediatric intensive care unit a diagnosis of severe neurological damage could lead to withdrawal of further intensive treatment. The severity of the brain damage was assessed by clinical neurological examination, cerebral magnetic resonance imaging and/or electroencephalography, and/or sensory evoked potentials. The combined results could lead to a decision to withdraw further intensive treatment. The paediatric cerebral performance category scale (PCPC)23 was used to qualify neurological outcome. This scale rates the neurological outcome by cognitive impairment in six categories: good neurological performance, mild neurological disability, moderate neurological disability, severe neurological disability, coma or vegetative state, and brain death.23 A good outcome was characterised by a PCPC score 3 at one year after the incident. Although fake hermes leather handbags it can be debated whether patients with a score of 3, who will require assistance in daily activities, really have a good outcome, we chose this conservative cut off point to be able to classify extremely poor outcome beyond discussion. We therefore defined poor outcome as death or survival with severe neurological disability at one year after the incident (score 4).
Statistical analysesContinuous data are presented as medians and interquartile range. Dichotomous and categorical data are presented as proportions, percentages of total, and 95% confidence intervals. We used Fisher's exact test for categorical data and Mann Whitney U test for continuous data. P
ResultsDescription of study populationFrom 1993 to 2012, 784 children were identified by the ICD 9 code for drowning. Two of the eight university medical centres were unable to identify children who died at the emergency department. Medical records were available for 753 children. Seventeen children were misclassified, thus 736 children were retained in the database, of whom 207 (28%) experienced cardiac arrest requiring advanced life support. Of these 207 children, 47 (47/207, 23%) were excluded from the present study: 25 had an initial body temperature of 34C, 14 were involved in a vehicle or boat incident, and eight drowned indoors.
We concentrated on the 160 children who experienced a cardiac arrest with hypothermia after drowning outside, which was not associated with a motor vehicle or boat incident. Figure 1 shows the flow of the 160 included children from the emergency department onwards and their subsequent clinical outcome. Of these children, 104 (65%) had ongoing cardiac arrest on arrival at the emergency department. All 98 children in whom return of spontaneous circulation was not achieved within 30 minutes received prolonged resuscitation. Of these 98 children, 23 children died in the emergency department. The 137 other children, in whom return of spontaneous circulation was achieved, were admitted to the paediatric intensive care unit (137/160, 86%), where 79 died (79/137; 58%, 95% confidence interval 50% to 66%); 30 had a diagnosis of brain death (30/79; 38%, 27% to 49%) and 27 had a diagnosis of severe neurological damage (27/79; 34%, 24% to 44%), the 22 others died of cardiac arrest, acute respiratory distress syndrome, or multi organ failure (22/79; 28%, 18% to 38%). In the original 160 children, the total mortality rate after cardiac arrest with hypothermia was 73% (66% to 80%; n=116). Ten children remained in a vegetative state (10/160; 6%, 2% to 10%), and 17 had severe neurological damage (17/160; 11%, 6% to 16%). One year after the drowning accident 17 children had a PCPC score of 3 (17/160; 11%, 6% to 16%).
Fig 1 flow and clinical outcome of children who drowned with cardiac arrest and hypothermia after presentation at emergency department. Final outcome was one year after drowning incident and categorised with paediatric cerebral performance categories (PCPC). Death, vegetative state, and severe disability were categorised as poor outcome. ROSC=return of spontaneous circulation, PICU=paediatric intensive care unit
Prolonged resuscitationProlonged resuscitation was performed in 98 of the 160 children with a cardiac arrest and hypothermia (61%, 95% confidence interval 54% to 69%). The outcome was not good in any of the children who underwent resuscitation beyond 30 minutes (0% with good outcome, 0% to 3%) (fig 3). Seventeen of the children who did not require prolonged resuscitation survived with a PCPC score 3 after one year (17/62 good outcome; 27%, 16% to 38%). The maximum duration of resuscitation with good outcome was 25 minutes. The outcome of prolonged resuscitation was extremely poor: 87 of the 98 children died (89%, 83% to 95%), and 11 survived in a vegetative state or with severe neurological damage (11%, 5% to 17%). Table 4 shows the characteristics of the children in relation to duration of resuscitation. Extracorporeal life support was performed in 12 children, of whom 11 died and one survived in a vegetative state. Thus, no child who underwent prolonged resuscitation, with or without extracorporeal life support, had a good outcome.
Initial cardiac arrest rhythmWe were able to retrieve data on the initial cardiac arrest rhythm from the medical records in 118 of the 160 children (74%). Asystole was diagnosed in nearly all children (101/118, 86%), followed by bradycardia (15/118, 13%) and ventricular fibrillation (2/118, 2%). Bradycardia correlated strongly with good outcome: six of the 15 children with bradycardia had good outcome versus eight of the 101 children with asystole (40% (95% confidence interval 15% to 65%) v 8% (3% to 13%); odds ratio 7.8 (2.2 to 27.3), P=0.001).
Duration of submersion, doses of adrenaline, and blood gas abnormalitiesIn only 3% of the cases (5/160) was the drowning incident witnessed by an adult, and consequently the duration of submersion was not precisely known in most cases. The typical history of most incidents was a sudden realisation of the child's absence, followed by an immediate search by the caretaker. Though the duration of the search was reasonably well known, it was usually unknown how long the child had been out of sight. The median estimated minimum and maximum durations of submersion correlated negatively with outcome (table 3). The longest estimated duration of submersion with good outcome was 25 minutes. Figure 6 shows the relation between maximum estimated submersion duration and outcome.
The median total number of doses of adrenaline administered was negatively associated with outcome (table 3). The median initial pH and the base excess were significantly lower in children with poor outcome (table 3). All children were manually or mechanically ventilated at the time of the initial blood gas measurement, while some children were still being resuscitated and others already had return of spontaneous circulation. The lowest pH associated with good a outcome was 6.75.
Treatment changesWe performed a subanalysis to determine whether changes in treatment during the study period affected the main outcomes. The percentage of children with good outcome in the first five years of the study period was comparable with the percentage in the last five years (7/51, 14% (95% confidence interval 4% to 23%) v 5/30, 17% (3% to 30%), P=0.75).
DiscussionImplication of key findingsIn children with cardiac arrest and hypothermia after drowning the necessity for resuscitation for more than 30 minutes did not result in good outcome in any child: 89% of children died and 11% survived in a vegetative state or with severe neurological damage. The study used a nationwide database over the period 1993 2012. Most children drowned during spring, summer, or autumn and had a much poorer outcome than those who drowned in winter. These results strongly question the therapeutic value of prolonged resuscitation in drowned children with cardiac arrest and hypothermia.
Participants Children aged up to 16 with cardiac arrest and hypothermia after drowning, who presented at emergency departments and/or were admitted to intensive care.
Main outcome measure Survival and neurological outcome one year after the drowning incident. Poor outcome was defined as death or survival in a vegetative state or with severe neurological disability (paediatric cerebral performance category (PCPC) 4).
Results From 1993 to 2012, 160 children presented with cardiac arrest and hypothermia after drowning. In 98 (61%) of these children resuscitation was performed for more than 30 minutes (98/160, median duration 60 minutes), of whom 87 (89%) died (95% confidence interval 83% to 95%; 87/98). Eleven of the 98 children survived (11%, 5% to 17%), but all had a PCPC score 4. In the 62 (39%) children who did not require prolonged resuscitation, 17 (27%, 16% to 38%) survived with a PCPC score 3 after one year: 10 (6%) had a good neurological outcome (score 1), five (3%) had mild neurological disability (score 2), and two (1%) had moderate neurological disability (score 3). From the original 160 children, only 44 were alive at one year with any outcome.
Conclusions Drowned children in whom return of spontaneous circulation is not achieved within 30 minutes of advanced life support have an extremely poor outcome. Good neurological outcome is more likely when spontaneous circulation returns within 30 minutes of advanced life support, especially when the drowning incident occurs in winter. These findings question the therapeutic value of resuscitation beyond 30 minutes in drowned children with cardiac arrest and hypothermia. Many houses are built near to ponds, ditches, or canals. A temperate maritime climate prevails, with mean air temperatures of 3.5C in winter, 9.5C in spring, 10.6C in autumn, and 17.0C in summer and water temperatures ranging from 0 8C in winter, 6 18C in spring and autumn, and 15 28C in summer.19 20
The Dutch emergency medical service has a legally enforced arrival time of less than 15 minutes for medical emergencies.21 All ambulance teams consist of a nurse trained in paediatric basic and advanced life support and allowed to perform intubation and administration of adrenaline (epinephrine) in children and a driver trained in paediatric basic life support. In cases of a cardiac arrest, a second emergency medical team is always called on, and, since 1999, this second team is often the helicopter emergency medical service with a physician on board.
Prehospital treatment is provided by emergency medical service nurses according to Dutch national ambulance protocols. These protocols are in accordance with the guidelines of the European Resuscitation Council. The national ambulance protocols how much is a hermes handbag instruct that all children with cardiac arrest and hypothermia should be transported, under continuous cardiopulmonary resuscitation, to a hospital with facilities for extracorporeal life support. The physicians of the helicopter emergency medical service and the emergency department treat according to the replica hermes birkin handbags guidelines of the Dutch Resuscitation Council and the European Resuscitation Council. All children with return of spontaneous circulation after prolonged resuscitation, whether primarily presented at the emergency department of a general hospital or a university medical centre, are transferred to a paediatric intensive care unit in one of the eight university medical centres.
PatientsWe retrospectively identified eligible patients by using the ICD 9 (international classification of diseases, ninth edition) code for drowning (994.1). For those aged 16 and under, their demographical and clinical data were entered in the database when they were admitted at the emergency department, the general paediatric ward, or the paediatric intensive care unit of one of the eight university medical centres from 1 January 1993 to 1 January 2012. Children who presented at the emergency department of a general hospital and transferred to the paediatric intensive care unit were included in this database.
Inclusion and exclusion criteriaWe included children with cardiac arrest after drowning outside (excluding heated outdoor swimming pools) and an initial core body temperature below 34C. Drowning outside was an inclusion criterion so hermes replica we could use season as a proxy for water temperature. As concurrent traumatic injuries could possibly influence outcome, we excluded children who drowned in a traffic or boating incident.
VariablesThe data collection was based on the Utstein style variables for uniform reporting of data from drowning.22 Data collected at the arrival of the emergency medical service included initial cardiac arrest rhythm, the use of bag and mask ventilation, intubation, duration of chest compressions, and number of doses of adrenaline and attempts at defibrillation. Data collected at the emergency department included initial core body temperature, score on Glasgow coma scale, the use of bag and mask ventilation, intubation, duration of chest compressions, number of doses of adrenaline, use of extracorporeal life support for cardiac arrest, and return of spontaneous circulation or death. Data collected at the paediatric intensive care unit included death or discharge, the cause of death, and, if applicable, the withdrawal of life sustaining treatment. Final disposition was dead or alive at one year after the drowning incident, and, if alive, the neurological status according to the paediatric cerebral performance category score (PCPC).23
DefinitionsThe minimum and maximum durations of submersion were taken from the medical records and were based on estimations by the caretaker(s) of the child at the time of incident. Cardiac arrest was defined as the necessity for chest compressions on arrival of the emergency medical service or and/or helicopter emergency medical service. The start point of the resuscitation time was marked by the initiation of chest compressions by the emergency services and the total duration of resuscitation included prehospital and in hospital advanced life support but excluded bystander cardiopulmonary resuscitation. Prolonged resuscitation was defined as more than 30 minutes of total resuscitation. This cut off was chosen because the mean attempted resuscitation time in many studies concerning resuscitation in children with out of hospital cardiac arrest averaged 30 minutes.24 We defined spring as the period between 1 March and 31 May, summer between 1 June and 31 August, autumn between 1 September and 30 November, and winter between 1 December and 29 February.
Initial cardiac arrest rhythm was the first rhythm visible after connection of the patient to the electrocardiograph of the emergency medical services. Initial temperature was defined as the first body temperature measured within one hour after arrival at the emergency department and concerned measurements of rectal or oesophageal temperature with a low reading thermometer. The initial blood gas analysis was measured within two hours after arrival at the emergency department. The term extracorporeal life support was used to indicate both extracorporeal circulation and extracorporeal membrane oxygenation. In the paediatric intensive care unit a diagnosis of severe neurological damage could lead to withdrawal of further intensive treatment. The severity of the brain damage was assessed by clinical neurological examination, cerebral magnetic resonance imaging and/or electroencephalography, and/or sensory evoked potentials. The combined results could lead to a decision to withdraw further intensive treatment. The paediatric cerebral performance category scale (PCPC)23 was used to qualify neurological outcome. This scale rates the neurological outcome by cognitive impairment in six categories: good neurological performance, mild neurological disability, moderate neurological disability, severe neurological disability, coma or vegetative state, and brain death.23 A good outcome was characterised by a PCPC score 3 at one year after the incident. Although fake hermes leather handbags it can be debated whether patients with a score of 3, who will require assistance in daily activities, really have a good outcome, we chose this conservative cut off point to be able to classify extremely poor outcome beyond discussion. We therefore defined poor outcome as death or survival with severe neurological disability at one year after the incident (score 4).
Statistical analysesContinuous data are presented as medians and interquartile range. Dichotomous and categorical data are presented as proportions, percentages of total, and 95% confidence intervals. We used Fisher's exact test for categorical data and Mann Whitney U test for continuous data. P
ResultsDescription of study populationFrom 1993 to 2012, 784 children were identified by the ICD 9 code for drowning. Two of the eight university medical centres were unable to identify children who died at the emergency department. Medical records were available for 753 children. Seventeen children were misclassified, thus 736 children were retained in the database, of whom 207 (28%) experienced cardiac arrest requiring advanced life support. Of these 207 children, 47 (47/207, 23%) were excluded from the present study: 25 had an initial body temperature of 34C, 14 were involved in a vehicle or boat incident, and eight drowned indoors.
We concentrated on the 160 children who experienced a cardiac arrest with hypothermia after drowning outside, which was not associated with a motor vehicle or boat incident. Figure 1 shows the flow of the 160 included children from the emergency department onwards and their subsequent clinical outcome. Of these children, 104 (65%) had ongoing cardiac arrest on arrival at the emergency department. All 98 children in whom return of spontaneous circulation was not achieved within 30 minutes received prolonged resuscitation. Of these 98 children, 23 children died in the emergency department. The 137 other children, in whom return of spontaneous circulation was achieved, were admitted to the paediatric intensive care unit (137/160, 86%), where 79 died (79/137; 58%, 95% confidence interval 50% to 66%); 30 had a diagnosis of brain death (30/79; 38%, 27% to 49%) and 27 had a diagnosis of severe neurological damage (27/79; 34%, 24% to 44%), the 22 others died of cardiac arrest, acute respiratory distress syndrome, or multi organ failure (22/79; 28%, 18% to 38%). In the original 160 children, the total mortality rate after cardiac arrest with hypothermia was 73% (66% to 80%; n=116). Ten children remained in a vegetative state (10/160; 6%, 2% to 10%), and 17 had severe neurological damage (17/160; 11%, 6% to 16%). One year after the drowning accident 17 children had a PCPC score of 3 (17/160; 11%, 6% to 16%).
Fig 1 flow and clinical outcome of children who drowned with cardiac arrest and hypothermia after presentation at emergency department. Final outcome was one year after drowning incident and categorised with paediatric cerebral performance categories (PCPC). Death, vegetative state, and severe disability were categorised as poor outcome. ROSC=return of spontaneous circulation, PICU=paediatric intensive care unit
Prolonged resuscitationProlonged resuscitation was performed in 98 of the 160 children with a cardiac arrest and hypothermia (61%, 95% confidence interval 54% to 69%). The outcome was not good in any of the children who underwent resuscitation beyond 30 minutes (0% with good outcome, 0% to 3%) (fig 3). Seventeen of the children who did not require prolonged resuscitation survived with a PCPC score 3 after one year (17/62 good outcome; 27%, 16% to 38%). The maximum duration of resuscitation with good outcome was 25 minutes. The outcome of prolonged resuscitation was extremely poor: 87 of the 98 children died (89%, 83% to 95%), and 11 survived in a vegetative state or with severe neurological damage (11%, 5% to 17%). Table 4 shows the characteristics of the children in relation to duration of resuscitation. Extracorporeal life support was performed in 12 children, of whom 11 died and one survived in a vegetative state. Thus, no child who underwent prolonged resuscitation, with or without extracorporeal life support, had a good outcome.
Initial cardiac arrest rhythmWe were able to retrieve data on the initial cardiac arrest rhythm from the medical records in 118 of the 160 children (74%). Asystole was diagnosed in nearly all children (101/118, 86%), followed by bradycardia (15/118, 13%) and ventricular fibrillation (2/118, 2%). Bradycardia correlated strongly with good outcome: six of the 15 children with bradycardia had good outcome versus eight of the 101 children with asystole (40% (95% confidence interval 15% to 65%) v 8% (3% to 13%); odds ratio 7.8 (2.2 to 27.3), P=0.001).
Duration of submersion, doses of adrenaline, and blood gas abnormalitiesIn only 3% of the cases (5/160) was the drowning incident witnessed by an adult, and consequently the duration of submersion was not precisely known in most cases. The typical history of most incidents was a sudden realisation of the child's absence, followed by an immediate search by the caretaker. Though the duration of the search was reasonably well known, it was usually unknown how long the child had been out of sight. The median estimated minimum and maximum durations of submersion correlated negatively with outcome (table 3). The longest estimated duration of submersion with good outcome was 25 minutes. Figure 6 shows the relation between maximum estimated submersion duration and outcome.
The median total number of doses of adrenaline administered was negatively associated with outcome (table 3). The median initial pH and the base excess were significantly lower in children with poor outcome (table 3). All children were manually or mechanically ventilated at the time of the initial blood gas measurement, while some children were still being resuscitated and others already had return of spontaneous circulation. The lowest pH associated with good a outcome was 6.75.
Treatment changesWe performed a subanalysis to determine whether changes in treatment during the study period affected the main outcomes. The percentage of children with good outcome in the first five years of the study period was comparable with the percentage in the last five years (7/51, 14% (95% confidence interval 4% to 23%) v 5/30, 17% (3% to 30%), P=0.75).
DiscussionImplication of key findingsIn children with cardiac arrest and hypothermia after drowning the necessity for resuscitation for more than 30 minutes did not result in good outcome in any child: 89% of children died and 11% survived in a vegetative state or with severe neurological damage. The study used a nationwide database over the period 1993 2012. Most children drowned during spring, summer, or autumn and had a much poorer outcome than those who drowned in winter. These results strongly question the therapeutic value of prolonged resuscitation in drowned children with cardiac arrest and hypothermia.
What do the world's one percent wear on their wrists
Richard Mile RM 69 Erotic Tourbillon ($507,700) 12 luxury brands debuted new watches and extensions of new lines at Watches and Wonders 2015. Are "erotic" watches the next big thing? A visit to Richard Mille's booth would indicate so. Richard Mille's RM69 features a series of provocative messages on the watch face, which rotate to show one message after the other. There are 169 messages in total, and can rotate by pushing a button located near the 10 o'clock hour. Messages include "let me kiss you tonight" and "I long to explore your lips." Those are the more kid friendly combinations.
Cartier Mysterious Double Tourbillon, Minute Repeater Tourbillon, Astrocalendar ($709,700 appoximately) Cartier unveiled a limited edition box (there are only a total of five available) that features three standout watches, each said to exemplify Cartier's watchmaking identity. The Mysterious Double Tourbillon, which features a rotating tourbillon at the heart of the watch; the Minute Repeater Tourbillon, which combines the Flying Tourbillon with a Minute Repeater; and the Astrocalendar, which features a complex calendar system that can differentiate between a normal year and a leap year.
2Hong Kong (CNN)This week, Hong Kong plays host to Watches and Wonders, an exhibition organized by the Fondation de la Haute Horlogerie (FHH).
Described by the event organizer and FHH Managing Director Fabienne Lupo as "a total immersion experience," the exhibition is less a trade men fake cartier ring fair and more a platform for education and culture.
Held at the Hong Kong Convention and Exhibition Center, the third annual Watches and Wonders features 12 fine watch maisons, 10 of which are owned by Swiss luxury group, Richemont.
Last year, the event recorded 16,000 invite only guests over four days, despite pro democracy Umbrella Movement protests deterring mainland Chinese tourists from visiting Hong Kong and disrupting traffic.
Peninsula Hotel Hong Kong, 9:00 am. Exciting day ahead! Visit us at WatchesandWonders 2015 to discover all the watch novelties. But, according to Deloitte's Swiss Watch cartier bangle bracelet replica Industry Study, only 27% of Swiss watch executives who responded to its annual survey, expect growth in China and Hong Kong over the next twelve months, with 34% expecting demand for Swiss watches to decline.
"It's why you will see everyone in the industry here the presence of all the brands' CEOs, the designers, even the watchmakers we want to show support during this uncertain period," Lupo explains.
As part of its educational element, the fair offered classes on watchmaking.
New features, like the addition of scannable QR codes that connect to audio tours, dot the exhibition space as a digital and Asia facing means to learn more about individual watches and brands' histories. Lectures, such as "Chinese people's aesthetic approach to watches" and watchmaking workshops, are on offer.
Branded booths range from loud to the uber chic
Our first stop is Swiss watch manufacturer, Roger Dubuis. And at 10am, it's a jarring wake up call. At only 20 years old, Dubuis is among the youngest brands in among the industry's old heritage maisons. As if to hammer this point home, the company has dramatically decked out its exhibition space which is transformed to feel like the mechanical insides of one of its skeleton watches.
WATCHES : 2 more days to go! Come and enjoy the Astral Skeleton Experience with Oculus glasses! Redeem your personal e invitation by clicking the link on our bio.
Jean Marc Pontroue, CEO of Roger Dubuis, says the exhibition's theatrics embody the brand's values. "We love fantasy. We love to enrich the brand with storytelling, with an emotional environment."
"We're targeting the young generation that don't necessarily want a classic watch, or the watch of their fathers," Pontroue continues. "But rather, the youth who like to wear niche brands."
What's it like to be inside a skeleton watch? Swiss manufacturer Roger Dubuis chose a bolder design for their exhibition space.
Pontroue admits that sales have been affected in Hong Kong and Macau this year, due to lower tourism numbers, but has remained cartier fake love ring gold stable in mainland China. In fact, the brand is expanding its presence in Beijing with a second store that opened this summer and another one planned for next year.
A polar opposite to the Gotham esque Roger Dubuis, is German watch manufacturer A. Lange Sohne which has chosen to present a more subdued set up.
"We didn't want to overshadow the watch," explains Katharina Mack, Head of Marketing at A. Lange Sohne. "It's about substance. It's not the staging that is emotional, it's the watch that is emotional."
Richard Mile RM 69 Erotic Tourbillon ($507,700) 12 luxury brands debuted new watches and extensions of new lines at Watches and Wonders 2015. Are "erotic" watches the next big thing? A visit to Richard Mille's booth would indicate so. Richard Mille's RM69 features a series of provocative messages on the watch face, which rotate to show one message after the other. There are 169 messages in total, and can rotate by pushing a button located near the 10 o'clock hour. Messages include "let me kiss you tonight" and "I long to explore your lips." Those are the more kid friendly combinations.
Cartier Mysterious Double Tourbillon, Minute Repeater Tourbillon, Astrocalendar ($709,700 appoximately) Cartier unveiled a limited edition box (there are only a total of five available) that features three standout watches, each said to exemplify Cartier's watchmaking identity. The Mysterious Double Tourbillon, which features a rotating tourbillon at the heart of the watch; the Minute Repeater Tourbillon, which combines the Flying Tourbillon with a Minute Repeater; and the Astrocalendar, which features a complex calendar system that can differentiate between a normal year and a leap year.
2Hong Kong (CNN)This week, Hong Kong plays host to Watches and Wonders, an exhibition organized by the Fondation de la Haute Horlogerie (FHH).
Described by the event organizer and FHH Managing Director Fabienne Lupo as "a total immersion experience," the exhibition is less a trade men fake cartier ring fair and more a platform for education and culture.
Held at the Hong Kong Convention and Exhibition Center, the third annual Watches and Wonders features 12 fine watch maisons, 10 of which are owned by Swiss luxury group, Richemont.
Last year, the event recorded 16,000 invite only guests over four days, despite pro democracy Umbrella Movement protests deterring mainland Chinese tourists from visiting Hong Kong and disrupting traffic.
Peninsula Hotel Hong Kong, 9:00 am. Exciting day ahead! Visit us at WatchesandWonders 2015 to discover all the watch novelties. But, according to Deloitte's Swiss Watch cartier bangle bracelet replica Industry Study, only 27% of Swiss watch executives who responded to its annual survey, expect growth in China and Hong Kong over the next twelve months, with 34% expecting demand for Swiss watches to decline.
"It's why you will see everyone in the industry here the presence of all the brands' CEOs, the designers, even the watchmakers we want to show support during this uncertain period," Lupo explains.
As part of its educational element, the fair offered classes on watchmaking.
New features, like the addition of scannable QR codes that connect to audio tours, dot the exhibition space as a digital and Asia facing means to learn more about individual watches and brands' histories. Lectures, such as "Chinese people's aesthetic approach to watches" and watchmaking workshops, are on offer.
Branded booths range from loud to the uber chic
Our first stop is Swiss watch manufacturer, Roger Dubuis. And at 10am, it's a jarring wake up call. At only 20 years old, Dubuis is among the youngest brands in among the industry's old heritage maisons. As if to hammer this point home, the company has dramatically decked out its exhibition space which is transformed to feel like the mechanical insides of one of its skeleton watches.
WATCHES : 2 more days to go! Come and enjoy the Astral Skeleton Experience with Oculus glasses! Redeem your personal e invitation by clicking the link on our bio.
Jean Marc Pontroue, CEO of Roger Dubuis, says the exhibition's theatrics embody the brand's values. "We love fantasy. We love to enrich the brand with storytelling, with an emotional environment."
"We're targeting the young generation that don't necessarily want a classic watch, or the watch of their fathers," Pontroue continues. "But rather, the youth who like to wear niche brands."
What's it like to be inside a skeleton watch? Swiss manufacturer Roger Dubuis chose a bolder design for their exhibition space.
Pontroue admits that sales have been affected in Hong Kong and Macau this year, due to lower tourism numbers, but has remained cartier fake love ring gold stable in mainland China. In fact, the brand is expanding its presence in Beijing with a second store that opened this summer and another one planned for next year.
A polar opposite to the Gotham esque Roger Dubuis, is German watch manufacturer A. Lange Sohne which has chosen to present a more subdued set up.
"We didn't want to overshadow the watch," explains Katharina Mack, Head of Marketing at A. Lange Sohne. "It's about substance. It's not the staging that is emotional, it's the watch that is emotional."
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Northridge Hospital Gives Parents Another Option
When Debbie Koslowsky's 6 year old son Alex was too sick to go to school, she would bring him to work to lie on the floor of her office at the West Valley YMCA in Reseda, or she would stay home with him.
Since Northridge Hospital Medical Center opened its Kids Care program for mildly sick children, she has another option, which she has used twice in the past six weeks, when Alex had two cases of strep throat.
"The last time Alex was there, I was wondering if he could also have an ear infection. The doctor checked Alex at no charge, which not only saved me the trouble and the $44 cost of going to the pediatrician after work, but I knew that if he had had a problem, I would have known about it early in the day," said Koslowsky, 38, a physical education director.
The Northridge Kids Care program, open since November, is set up to care for mildly sick children, from 6 weeks to 15 years old, 24 hours a day, at a cost of $3.25 per hour, or $2.75 for hospital employees.
The program, which operates as an outpatient service under Northridge's hospital license, "does not accept children for Kids Care who have chicken pox, lice, measles or high temperatures that are not responding to Tylenol," said Cindy Albright, a registered nurse and coordinator for Kids Care. Parents do not have to call ahead to say they are bringing a child in, but it is encouraged, and pre registration forms that include the child's medical history help speed the 10 minute registration process.
One hospital staff nursing assistant is assigned to care for every four children. Registered nurses oversee the care and give the necessary Hermes bag copy medications, either over the counter drugs or medications already prescribed for the child. Physicians from the hospital's UCLA Family Residency Program examine the children each morning and notify parents if they find medical problems that they think need more evaluation.
The Kids Care facilities, in the pediatric wing on the fifth floor of the hospital, are divided into bag Hermes fake a quiet room, a crafts room and a kitchen. Most children become involved in crafts, directed by a part time child activities coordinator, or take the video route, playing an ever popular Nintendo game or watching TV and videotapes. Some bring their own treasured blankets, backpacks, books, dolls or other toys.
Carrie Reitz, 12, was recently at Kids Care after a night of high fever and an upset stomach. Although Carrie was feeling better, her mother hesitated to let her go to school. The day she was at Kids Care, she played with the other three children there, who were from 1 to 8 years old.
Was it scary to come to a hospital for the day? "No," she said. "I wasn't real sure when I came in. There's a lot of things to do. You can read books, help the little kids color. . . . It's better than home."
Carrie's mother, Beverly, is a teacher at First Lutheran Pre School across the street from the hospital. "Parents who work tend to bring their children to the nursery school even if the children are not 100%," she said. She thinks that the hospital's program provides the added care and reassurance parents need to leave their children to go to work.
Started for Employees
According to Don Adams, administrator of Northridge Hospital, the Kids Care program was started largely to attract and fake Hermes Kelly handbag retain hospital employees. Northridge Hospital and Valley Hospital Medical Center in Van Nuys, both owned by Hospital Corp. of America, employ a total of 1,600 people, Adams said. The center cares for an average of four or five children a day.
Two hermes replica bag Los Angeles hospitals California Medical Center and Orthopaedic Hospital have recently closed their sick child care programs. Another, at Torrance Memorial Medical Center, the model for Northridge's program, is going strong, caring for an average of five to 18 children a day.
Patsy Lane, child care coordinator for the city of Los Angeles, said closure of these programs may be because "it's hard for people to bring an ill child to a place that's relatively unfamiliar. It's a tough concept for parents to bring their children for day care to a health care facility."
Lane said the most successful sick child care programs have been in suburban areas, geographically and administratively connected to the sick child's regular day care or nursery school program. On a sick day, the child doesn't go to an entirely different place, just to a different room or wing at the same school. But she thinks that the license requirements for such programs mildly ill day care children are kept separate from hospital patients, and employees who care for the day care children do not also care for hospitalized children minimize the risks.
When Debbie Koslowsky's 6 year old son Alex was too sick to go to school, she would bring him to work to lie on the floor of her office at the West Valley YMCA in Reseda, or she would stay home with him.
Since Northridge Hospital Medical Center opened its Kids Care program for mildly sick children, she has another option, which she has used twice in the past six weeks, when Alex had two cases of strep throat.
"The last time Alex was there, I was wondering if he could also have an ear infection. The doctor checked Alex at no charge, which not only saved me the trouble and the $44 cost of going to the pediatrician after work, but I knew that if he had had a problem, I would have known about it early in the day," said Koslowsky, 38, a physical education director.
The Northridge Kids Care program, open since November, is set up to care for mildly sick children, from 6 weeks to 15 years old, 24 hours a day, at a cost of $3.25 per hour, or $2.75 for hospital employees.
The program, which operates as an outpatient service under Northridge's hospital license, "does not accept children for Kids Care who have chicken pox, lice, measles or high temperatures that are not responding to Tylenol," said Cindy Albright, a registered nurse and coordinator for Kids Care. Parents do not have to call ahead to say they are bringing a child in, but it is encouraged, and pre registration forms that include the child's medical history help speed the 10 minute registration process.
One hospital staff nursing assistant is assigned to care for every four children. Registered nurses oversee the care and give the necessary Hermes bag copy medications, either over the counter drugs or medications already prescribed for the child. Physicians from the hospital's UCLA Family Residency Program examine the children each morning and notify parents if they find medical problems that they think need more evaluation.
The Kids Care facilities, in the pediatric wing on the fifth floor of the hospital, are divided into bag Hermes fake a quiet room, a crafts room and a kitchen. Most children become involved in crafts, directed by a part time child activities coordinator, or take the video route, playing an ever popular Nintendo game or watching TV and videotapes. Some bring their own treasured blankets, backpacks, books, dolls or other toys.
Carrie Reitz, 12, was recently at Kids Care after a night of high fever and an upset stomach. Although Carrie was feeling better, her mother hesitated to let her go to school. The day she was at Kids Care, she played with the other three children there, who were from 1 to 8 years old.
Was it scary to come to a hospital for the day? "No," she said. "I wasn't real sure when I came in. There's a lot of things to do. You can read books, help the little kids color. . . . It's better than home."
Carrie's mother, Beverly, is a teacher at First Lutheran Pre School across the street from the hospital. "Parents who work tend to bring their children to the nursery school even if the children are not 100%," she said. She thinks that the hospital's program provides the added care and reassurance parents need to leave their children to go to work.
Started for Employees
According to Don Adams, administrator of Northridge Hospital, the Kids Care program was started largely to attract and fake Hermes Kelly handbag retain hospital employees. Northridge Hospital and Valley Hospital Medical Center in Van Nuys, both owned by Hospital Corp. of America, employ a total of 1,600 people, Adams said. The center cares for an average of four or five children a day.
Two hermes replica bag Los Angeles hospitals California Medical Center and Orthopaedic Hospital have recently closed their sick child care programs. Another, at Torrance Memorial Medical Center, the model for Northridge's program, is going strong, caring for an average of five to 18 children a day.
Patsy Lane, child care coordinator for the city of Los Angeles, said closure of these programs may be because "it's hard for people to bring an ill child to a place that's relatively unfamiliar. It's a tough concept for parents to bring their children for day care to a health care facility."
Lane said the most successful sick child care programs have been in suburban areas, geographically and administratively connected to the sick child's regular day care or nursery school program. On a sick day, the child doesn't go to an entirely different place, just to a different room or wing at the same school. But she thinks that the license requirements for such programs mildly ill day care children are kept separate from hospital patients, and employees who care for the day care children do not also care for hospitalized children minimize the risks.
Word Wenches
Years published 164. Novels published 231. Novellas published 74. Range of story dates 9 centuries fake cartier love bracelet (1026 present). AWARDS WON: RWA RITA, RWA Honor Roll, RWA Top 10 Favorite, RT Lifetime Achievement, RT Living Legend, RT Reviewers Choice, Publishers Weekly Starred Reviews, Golden Leaf, Barclay Gold, ABA Notable Book, Historical Novels Review Editors Choice, AAR Best Romance, Smart Bitches Top 10, Kirkus Reviews Top 21, Library Journal Top 5, Publishers Weekly Top 5, Booklist Top 10, Booktopia Top 10, Golden Apple Award for Lifetime Achievement.
Nicola here. Today it is my very great pleasure to welcome Melinda Hammond back to the Word Wench blog. Today, however, we are chatting about her haunting timeslip novel Moonshadows, set in the Georgian period and the present day, originally published by Samhain and now re issued by Melinda herself.
I first read Moonshadows a number of years ago and found it a thought provoking read as well as a beautiful mix of the past and the present. In the interview below, Melinda mentions why she feels the story takes a different slant on the idea of the 18th century rake. The conflict at the heart of the story is strong and heartbreaking and (no spoilers!) tells of the ultimate price of getting what you wish for
Anne here. Since the loss of our beloved Jo, we wenches have been discussing who we would like join us in Word Wench bloggery. Amazingly because often making Word Wench decisions is a bit like trying to herd cats we were unanimous in our first choice. And when we asked her, we were thrilled when she said yes!
Her first blog will be on July 25th, and until then, we keeping her wrapped in mystery.
But here for your intrigue and entertainment is a quiz about her. Not that we tell you who won or what the answer is until the 24th July, but a prize for someone who makes a answer. get a pen and paper and note your answers, then click on the link at the bottom, and see how right you were or weren Then come back and make a guess about who you think the new Word Wench might be.
Mystery Wench Quiz: (and no, that not her below, it Greta Garbo in The Mysterious Lady)
by Mary Jo
Hi, there! Today we are lucky enough to welcome Karen Harper as a return guest. Karen has been writing even longer that I have , and she known for her versatility and superb research. She started out with historical romance and has since branched out into main stream historical, romantic thrillers (including contemporary Amish suspense), and historical mysteries. She isa winner of the Mary Higgins Clark award.
He most certainly was right on about the heroine of The Royal Nanny, Charlotte Bill, the Cockney woman who raised the children of King George V and Queen Mary, the current queen's grandparents.
Two of those six children became kings, and in a way, Charlotte, or 'Lala' as the children dubbed her, saved both of these boys. When she arrived in the royal household of the then Duke and Duchess of York, David (later King Edward VIII and Duke of Windsor) and Bertie (later King George VI) were being abused by their current nanny, who was later committed to an asylum. (Remember The King's Speech flashbacks where Bertie was ignored and starved? And why did the Duke of Windsor gravitate toward abusive, take charge women, including his beloved Wallis?)
Anne here, with Susanna Kearsley and dropping by celebrate our 10th anniversary with us. They also representative of international wenchdom, as Pam is from the UK and Susanna from Canada.
It's a thing about writing: so much of it needs to be done on your own in a room by yourself, shut away from distractions, that it would be easy to feel disconnectedif we didn't have this amazing community.
The first time I best replica cartier love bracelet reviews took my elder son to FanExpo here in in Toronto, he looked across the lines of people standing in their cosplay costumes waiting to get in, and said, "My people!" And I knew exactly how he felt. When I don't have to explain why I'd rather shut myself away with a pile of 18th century newspapers and a big pot of coffee than go to the mall. When I can say I've just surfaced from being in another time, and people understand. It's a wonderful feeling, to be understood.
It's in places like this one, with hosts like the Word Wenches, that we're all able to find one another. We cheer each other, teach each other, share our craft and learn in equal measure; and, as evidenced by this past week, we give each other comfort.
Back when I was gifted with my Honorary Word Wench title, on September 23 of 2009, this group was a mere three years old, and I only knew Nicola. then cartier fake mens ring diamond I've met nearly all of the Wenches, and from sharing an event with Joanna to sharing drinks and laughter with Anne, to having her and Mary Jo come and stand at my shoulder when I won my RITA, the Word Wenches really and truly are "My people". (Susanna first interview with the wenches is here.)
May they continue another ten years, and beyond that.
Susanna Kearsley
Susanna most recent publication is A Desperate Fortune Her website is here.
And now, here Hartshorne:
It is a great honour to be an Honorary Word Wench, especially when I spent so many years writing strictly contemporary romances for Mills Boon as Jessica Hart. But I have always been fascinated by the relationship between the past and the present, and in fact started writing to fund a PhD in medieval history (although I ended up as an early modernist) so my historical leanings have always been there.
Throughout the (very) many years it took me to complete that PhD, the question I was asked most often after 'Have you ever thought about writing a real book?', of course was whether I was going to use my research to write a historical romance. My answer was always 'no': I fretted about authenticity and how I could possibly get modern readers to identify with characters who thought and spoke and acted so differently in the past.
Years published 164. Novels published 231. Novellas published 74. Range of story dates 9 centuries fake cartier love bracelet (1026 present). AWARDS WON: RWA RITA, RWA Honor Roll, RWA Top 10 Favorite, RT Lifetime Achievement, RT Living Legend, RT Reviewers Choice, Publishers Weekly Starred Reviews, Golden Leaf, Barclay Gold, ABA Notable Book, Historical Novels Review Editors Choice, AAR Best Romance, Smart Bitches Top 10, Kirkus Reviews Top 21, Library Journal Top 5, Publishers Weekly Top 5, Booklist Top 10, Booktopia Top 10, Golden Apple Award for Lifetime Achievement.
Nicola here. Today it is my very great pleasure to welcome Melinda Hammond back to the Word Wench blog. Today, however, we are chatting about her haunting timeslip novel Moonshadows, set in the Georgian period and the present day, originally published by Samhain and now re issued by Melinda herself.
I first read Moonshadows a number of years ago and found it a thought provoking read as well as a beautiful mix of the past and the present. In the interview below, Melinda mentions why she feels the story takes a different slant on the idea of the 18th century rake. The conflict at the heart of the story is strong and heartbreaking and (no spoilers!) tells of the ultimate price of getting what you wish for
Anne here. Since the loss of our beloved Jo, we wenches have been discussing who we would like join us in Word Wench bloggery. Amazingly because often making Word Wench decisions is a bit like trying to herd cats we were unanimous in our first choice. And when we asked her, we were thrilled when she said yes!
Her first blog will be on July 25th, and until then, we keeping her wrapped in mystery.
But here for your intrigue and entertainment is a quiz about her. Not that we tell you who won or what the answer is until the 24th July, but a prize for someone who makes a answer. get a pen and paper and note your answers, then click on the link at the bottom, and see how right you were or weren Then come back and make a guess about who you think the new Word Wench might be.
Mystery Wench Quiz: (and no, that not her below, it Greta Garbo in The Mysterious Lady)
by Mary Jo
Hi, there! Today we are lucky enough to welcome Karen Harper as a return guest. Karen has been writing even longer that I have , and she known for her versatility and superb research. She started out with historical romance and has since branched out into main stream historical, romantic thrillers (including contemporary Amish suspense), and historical mysteries. She isa winner of the Mary Higgins Clark award.
He most certainly was right on about the heroine of The Royal Nanny, Charlotte Bill, the Cockney woman who raised the children of King George V and Queen Mary, the current queen's grandparents.
Two of those six children became kings, and in a way, Charlotte, or 'Lala' as the children dubbed her, saved both of these boys. When she arrived in the royal household of the then Duke and Duchess of York, David (later King Edward VIII and Duke of Windsor) and Bertie (later King George VI) were being abused by their current nanny, who was later committed to an asylum. (Remember The King's Speech flashbacks where Bertie was ignored and starved? And why did the Duke of Windsor gravitate toward abusive, take charge women, including his beloved Wallis?)
Anne here, with Susanna Kearsley and dropping by celebrate our 10th anniversary with us. They also representative of international wenchdom, as Pam is from the UK and Susanna from Canada.
It's a thing about writing: so much of it needs to be done on your own in a room by yourself, shut away from distractions, that it would be easy to feel disconnectedif we didn't have this amazing community.
The first time I best replica cartier love bracelet reviews took my elder son to FanExpo here in in Toronto, he looked across the lines of people standing in their cosplay costumes waiting to get in, and said, "My people!" And I knew exactly how he felt. When I don't have to explain why I'd rather shut myself away with a pile of 18th century newspapers and a big pot of coffee than go to the mall. When I can say I've just surfaced from being in another time, and people understand. It's a wonderful feeling, to be understood.
It's in places like this one, with hosts like the Word Wenches, that we're all able to find one another. We cheer each other, teach each other, share our craft and learn in equal measure; and, as evidenced by this past week, we give each other comfort.
Back when I was gifted with my Honorary Word Wench title, on September 23 of 2009, this group was a mere three years old, and I only knew Nicola. then cartier fake mens ring diamond I've met nearly all of the Wenches, and from sharing an event with Joanna to sharing drinks and laughter with Anne, to having her and Mary Jo come and stand at my shoulder when I won my RITA, the Word Wenches really and truly are "My people". (Susanna first interview with the wenches is here.)
May they continue another ten years, and beyond that.
Susanna Kearsley
Susanna most recent publication is A Desperate Fortune Her website is here.
And now, here Hartshorne:
It is a great honour to be an Honorary Word Wench, especially when I spent so many years writing strictly contemporary romances for Mills Boon as Jessica Hart. But I have always been fascinated by the relationship between the past and the present, and in fact started writing to fund a PhD in medieval history (although I ended up as an early modernist) so my historical leanings have always been there.
Throughout the (very) many years it took me to complete that PhD, the question I was asked most often after 'Have you ever thought about writing a real book?', of course was whether I was going to use my research to write a historical romance. My answer was always 'no': I fretted about authenticity and how I could possibly get modern readers to identify with characters who thought and spoke and acted so differently in the past.
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Pak briefs Hermes bag copy Diplomatic Corps in Islamabad on LoC tension
22:54 21 air raids slow IS advance near Kobane: US military: US led aircraft hammered Islamic State jihadists with 21 bombing raids near Kobane amid signs the strikes had Hermes Kelly bag fake "slowed" the group's advance on the Syrian border town, the American military said.
In one of the heaviest bombardments so far against the Sunni jihadists encircling Kobane yesterday and today, coalition air strikes "destroyed" two IS staging locations, a building, a truck, two vehicles, three compounds and damaged several other targets, it said.
22:53 J flood: General insurers submit status report to High Court: Insurance companies with huge exposure to flood hit J submitted their compliance reports to the Jammu and Kashmir (J High Court today.
"We have submitted our compliance report before the J High Court today in which we gave details of the number of claims we have already settled as well as the amounts paid against those claims so far," United Insurance Chairman and Managing Director Milind Kharat told PTI today without disclosing the total amount his company paid to claimants.
"We need to get Ebola under control in the near term so that it doesn't spread further and become a long term global health crisis that we end up fighting for decades at large scale, like HIV or polio. Mukherjee's 'The Lives Of Others', a sweeping account of life in 1960s Calcutta, is 5/2 favourite to win with bookmakers William Hill, making him the frontrunner for the coveted 50,000 pound prize to be presented by Camilla, Duchess of Cornwall, at a gala ceremony at London's Guildhall.
London based Mukherjee has been selected for his second novel published in May this year. The book is based in his birth place of Kolkata and centres around a dysfunctional Ghosh family in the 1960s and the secrets and rivalries within the family against a backdrop of political activism.
Mukerjee, who studied at Oxford and Cambridge Universities, reviews fiction for the 'Times' and the 'Sunday Telegraph' and his first novel, 'A Life Apart' was a joint winner of the Vodafone Crossword Award in India.
21:44 Bachchan appeals to all to contribute for Kashmir flood relief: Bollywood bag Hermes copy megastar Amitabh Bachchan today called on all the citizens of the country to show their support for Kashmir flood victims. Jammu and Kashmir was hit by heavy floods caused by torrential rains in September, which left at least 200 dead and thousands homeless.
Bachchan, while promoting a charity campaign 'HUM HAIN. Umeed e Kashmir' for the flood victims here, said, "As human beings and as Indians we need to do all that we can help our countrymen in need.
The plight of the people of Jammu and Kashmir has always been a matter of concern and the floods have only made it worse.
"All that we do simply won't be enough to meet the various challenges facing the people, but every drop counts. Hence we call on everyone in our country and from the world community to come forward and provide their support."
21:31 Bilawal Bhutto facing threats to life: Sindh govt: Pakistan People's Party chief Bilawal Bhutto Zardari is facing serious threats to his life from an outlawed militant group, a media report said today.
The government of Sindh has ordered law enforcement agencies "to ensure extreme vigilance" and take "special measures" to save Bilawal's life from Jundullah militant group, the Dawn reported.
The provincial government in what was intended as a confidential letter shared intelligence of a plan being made by the banned group to target the PPP chairperson. However, the leaked letter did not state the details regarding the date, time, place and method of the attack.
21:19 Prime Minister Narendra Modi's "man ki baat" address to the nation on October 3 on All India Radio (AIR) was listened by over 66 per cent of the people in six cities of the country. The survey was conducted randomly in Mumbai, Chennai, Ahmadabad, Bangalore, Bhopal and Trivandrum covering 100 listeners in each of these cities, said Director General of AIR F Sheharyar.
"It was found that 66.7 per cent of the people had listened to the PM's speech on AIR and they found it very useful," he said.
The transmission was also carried by several private TV channels and FM radios. Sheharyar also talked about AIR's plans to broadcast programmes which are run on medium wave on FM,l thus giving a new lease of life to the popular programmes aired on medium wave stations.
21:17 HC upholds former MLA Pappu Kalani's conviction in murder case: The Bombay high court today dismissed appeals filed by former Maharashtra MLA Suresh alias Pappu Kalani and three others against a sessions court verdict convicting them in a murder case.
The division bench of justices S C Dharmadhikari and Anil Menon dismissed the appeals, saying the court did not find anything perverse in the verdict convicting them for conspiracy and murder of Ghansham Bhatija. Bhatija was shot dead at Ulhasnagar in neighbouring Thane district on February 27, 1990.
His brother Inder bag Hermes fake Bhatija, who saw his brother being gunned down, was shot dead on April 28, 1990 despite having police protection. According to the police, the murders were fall out of a long standing political and criminal rivalry.
21:10 Actor Pawan Kalyan announces Rs 50 lakh for cyclone relief work: Telugu actor and founder president of Jana Sena Party Pawan Kalyan today announced Rs 50 lakh to the Chief Minister's relief fund for taking up relief operations in the aftermath of cyclone Hudhud in Andhra Pradesh.
"I am deeply anguished by the calamity that has swept through Vizag and North Andhra. The plight of lakhs of people who have been destabilised is unimaginable. My heart aches for them," Pawan Kalyan said in a release here.
"It is in times like these that we should step forward beyond parties and politics and come together as one force to overcome this calamity.
Even as all efforts are being made by the Central and State governments, as an individual I will be handing over Rs 50 lakh towards the CM Relief Fund," he added.
20:53 Statements in a blog are personal opinion which cannot be treated as an evidence, the Delhi High Court today said and dismissed a plea for a CBI probe into allegation by Justice (Rtd) Markandey Katju who had blogged that a former CJI had made "improper compromises" to favour a High Court judge despite adverse IB report against him.
22:54 21 air raids slow IS advance near Kobane: US military: US led aircraft hammered Islamic State jihadists with 21 bombing raids near Kobane amid signs the strikes had Hermes Kelly bag fake "slowed" the group's advance on the Syrian border town, the American military said.
In one of the heaviest bombardments so far against the Sunni jihadists encircling Kobane yesterday and today, coalition air strikes "destroyed" two IS staging locations, a building, a truck, two vehicles, three compounds and damaged several other targets, it said.
22:53 J flood: General insurers submit status report to High Court: Insurance companies with huge exposure to flood hit J submitted their compliance reports to the Jammu and Kashmir (J High Court today.
"We have submitted our compliance report before the J High Court today in which we gave details of the number of claims we have already settled as well as the amounts paid against those claims so far," United Insurance Chairman and Managing Director Milind Kharat told PTI today without disclosing the total amount his company paid to claimants.
"We need to get Ebola under control in the near term so that it doesn't spread further and become a long term global health crisis that we end up fighting for decades at large scale, like HIV or polio. Mukherjee's 'The Lives Of Others', a sweeping account of life in 1960s Calcutta, is 5/2 favourite to win with bookmakers William Hill, making him the frontrunner for the coveted 50,000 pound prize to be presented by Camilla, Duchess of Cornwall, at a gala ceremony at London's Guildhall.
London based Mukherjee has been selected for his second novel published in May this year. The book is based in his birth place of Kolkata and centres around a dysfunctional Ghosh family in the 1960s and the secrets and rivalries within the family against a backdrop of political activism.
Mukerjee, who studied at Oxford and Cambridge Universities, reviews fiction for the 'Times' and the 'Sunday Telegraph' and his first novel, 'A Life Apart' was a joint winner of the Vodafone Crossword Award in India.
21:44 Bachchan appeals to all to contribute for Kashmir flood relief: Bollywood bag Hermes copy megastar Amitabh Bachchan today called on all the citizens of the country to show their support for Kashmir flood victims. Jammu and Kashmir was hit by heavy floods caused by torrential rains in September, which left at least 200 dead and thousands homeless.
Bachchan, while promoting a charity campaign 'HUM HAIN. Umeed e Kashmir' for the flood victims here, said, "As human beings and as Indians we need to do all that we can help our countrymen in need.
The plight of the people of Jammu and Kashmir has always been a matter of concern and the floods have only made it worse.
"All that we do simply won't be enough to meet the various challenges facing the people, but every drop counts. Hence we call on everyone in our country and from the world community to come forward and provide their support."
21:31 Bilawal Bhutto facing threats to life: Sindh govt: Pakistan People's Party chief Bilawal Bhutto Zardari is facing serious threats to his life from an outlawed militant group, a media report said today.
The government of Sindh has ordered law enforcement agencies "to ensure extreme vigilance" and take "special measures" to save Bilawal's life from Jundullah militant group, the Dawn reported.
The provincial government in what was intended as a confidential letter shared intelligence of a plan being made by the banned group to target the PPP chairperson. However, the leaked letter did not state the details regarding the date, time, place and method of the attack.
21:19 Prime Minister Narendra Modi's "man ki baat" address to the nation on October 3 on All India Radio (AIR) was listened by over 66 per cent of the people in six cities of the country. The survey was conducted randomly in Mumbai, Chennai, Ahmadabad, Bangalore, Bhopal and Trivandrum covering 100 listeners in each of these cities, said Director General of AIR F Sheharyar.
"It was found that 66.7 per cent of the people had listened to the PM's speech on AIR and they found it very useful," he said.
The transmission was also carried by several private TV channels and FM radios. Sheharyar also talked about AIR's plans to broadcast programmes which are run on medium wave on FM,l thus giving a new lease of life to the popular programmes aired on medium wave stations.
21:17 HC upholds former MLA Pappu Kalani's conviction in murder case: The Bombay high court today dismissed appeals filed by former Maharashtra MLA Suresh alias Pappu Kalani and three others against a sessions court verdict convicting them in a murder case.
The division bench of justices S C Dharmadhikari and Anil Menon dismissed the appeals, saying the court did not find anything perverse in the verdict convicting them for conspiracy and murder of Ghansham Bhatija. Bhatija was shot dead at Ulhasnagar in neighbouring Thane district on February 27, 1990.
His brother Inder bag Hermes fake Bhatija, who saw his brother being gunned down, was shot dead on April 28, 1990 despite having police protection. According to the police, the murders were fall out of a long standing political and criminal rivalry.
21:10 Actor Pawan Kalyan announces Rs 50 lakh for cyclone relief work: Telugu actor and founder president of Jana Sena Party Pawan Kalyan today announced Rs 50 lakh to the Chief Minister's relief fund for taking up relief operations in the aftermath of cyclone Hudhud in Andhra Pradesh.
"I am deeply anguished by the calamity that has swept through Vizag and North Andhra. The plight of lakhs of people who have been destabilised is unimaginable. My heart aches for them," Pawan Kalyan said in a release here.
"It is in times like these that we should step forward beyond parties and politics and come together as one force to overcome this calamity.
Even as all efforts are being made by the Central and State governments, as an individual I will be handing over Rs 50 lakh towards the CM Relief Fund," he added.
20:53 Statements in a blog are personal opinion which cannot be treated as an evidence, the Delhi High Court today said and dismissed a plea for a CBI probe into allegation by Justice (Rtd) Markandey Katju who had blogged that a former CJI had made "improper compromises" to favour a High Court judge despite adverse IB report against him.
Q Science and Innovation Minister Paul Goldsmith
It's been two months since Paul Goldsmith filled Steven Joyce's shoes as Science and Innovation Minister. Science reporter Jamie Morton spoke with him about the state of the sector and some of our scientists' big concerns.There are some people who think we can just sit back and benefit from all the scientific advances around the world, but it's important that we contribute as well.We do in Niwa and I'm pretty determined that we continue to build on that and strengthen that and fake hermes leather handbags likewise in environment and in geological things.We live in a place with earthquakes and volcanoes and we have an economy based on pastoral industries, so I'm [also] pretty determined that we build on our real strengths in those areas.What will be your relationship be with how much is a hermes handbag the Prime Minister's chief science advisor, Professor Sir Peter Gluckman?Well, a good close working relationship.I've already had several conversations with him.I've known him for many years, independently, and he's a very good man and a very high quality scientist and a broad thinker.So I'm very fortunate to have a wide range of advice coming in from the MBIE [Ministry of Business, Innovation and Employment] as the fake Hermes bag maintenance lead government agency, but also from Sir Peter, and also from the many, many people involved in the Crown research institutes and universities.But it will be a close relationship.Do you think R is growing at a replica hermes bags outlet fast enough rate, and do you identify with the philosophy of your predecessor, Steven Joyce, that it drives the economy?Like I say, investment in R is absolutely an important part of building a more productive and competitive economy, which is the broader goal that we have.It's not the only thing, of course. Investment, more generally, is fundamental.But certainly, over time, lifting the research intensity of our economy into higher value products is a good thing, and certainly, that's why the Government has substantially increased its investment in R to nearly $1.3 billion a year, this year, and we are aiming to get to $1.6 billion by 2020.
It's been two months since Paul Goldsmith filled Steven Joyce's shoes as Science and Innovation Minister. Science reporter Jamie Morton spoke with him about the state of the sector and some of our scientists' big concerns.There are some people who think we can just sit back and benefit from all the scientific advances around the world, but it's important that we contribute as well.We do in Niwa and I'm pretty determined that we continue to build on that and strengthen that and fake hermes leather handbags likewise in environment and in geological things.We live in a place with earthquakes and volcanoes and we have an economy based on pastoral industries, so I'm [also] pretty determined that we build on our real strengths in those areas.What will be your relationship be with how much is a hermes handbag the Prime Minister's chief science advisor, Professor Sir Peter Gluckman?Well, a good close working relationship.I've already had several conversations with him.I've known him for many years, independently, and he's a very good man and a very high quality scientist and a broad thinker.So I'm very fortunate to have a wide range of advice coming in from the MBIE [Ministry of Business, Innovation and Employment] as the fake Hermes bag maintenance lead government agency, but also from Sir Peter, and also from the many, many people involved in the Crown research institutes and universities.But it will be a close relationship.Do you think R is growing at a replica hermes bags outlet fast enough rate, and do you identify with the philosophy of your predecessor, Steven Joyce, that it drives the economy?Like I say, investment in R is absolutely an important part of building a more productive and competitive economy, which is the broader goal that we have.It's not the only thing, of course. Investment, more generally, is fundamental.But certainly, over time, lifting the research intensity of our economy into higher value products is a good thing, and certainly, that's why the Government has substantially increased its investment in R to nearly $1.3 billion a year, this year, and we are aiming to get to $1.6 billion by 2020.
Phil Taylor wins first round match at Unibet Masters
Phil Taylor's last year on the PDC circuit began with victory over Michael Smith at the Unibet Masters, while Gary Anderson set up a clash with Raymond van Barneveld.
On Friday, Taylor reaffirmed what he had hinted at after his World Championship defeat to 'Barney' in December, that 2017 would be his last year on the circuit, with the 2018 World Championship being his last event.
The Power had admitted during the Worlds that he intended to just play the TV tournaments and the events that his ranking got him into during 2017, but confirmation of his impending retirement means the year will now become something of a farewell tour for the 16 time world champion
With the news out in the open, Taylor romped past Michael Smith, winning eight of the final 10 legs in Milton Keynes to seal a victory that sets up a quarter final date with third seed Peter Wright, who beat Ian White 10 5.
Unibet Masters First Round Friday's Results Dave Chisnall 5 10 Raymond van Barneveld Peter Taylor 10 6 Michael Smith Gary Anderson 10 3 Benito how much is a hermes handbag van de Pas Peter Wright 10 5 Ian White Saturday's Matches Mensur Suljovic 10 4 Jelle Klaasen James Wade 9 10 Robert Thornton Michael van Gerwen 10 6 Simon Whitlock Adrian Lewis 10 6 Kim Huybrechts
Taylor was delighted with his display and is looking forward to enjoying his final year on the circuit:
"I think I'm more excited now and I've got butterflies, whereas I didn't have that before. Perhaps that will do me good," he said.
Peter Wright will be up next for Taylor (Picture: Lawrence Lustig/PDC)
"This is a brilliant start. copy hermes bags I've got new darts and they were going lovely. I missed a few doubles and I went 4 2 down and clambered back to five each, and then I had a chance and double seven was lovely tonight."
World number two Gary Anderson produced the most impressive performance of the opening night, averaging almost 110 in a 10 3 demolition of Masters debutant Benito van de Pas.
Van de Pas weathered an early barrage from Anderson to land an 11 darter as he stayed in touch at 3 2, but the two time world champion reeled off the next five legs without reply before bettering the Dutchman's 128 fake hermes leather handbags checkout with a 142 finish to wrap up the win.
"I've had two weeks off since the World Championship without throwing a dart and it's worked," said Anderson.
"I've had a break and it's been great. I've enjoyed the couple of weeks back at home but I've got my head back on now and we'll see what happens."
Up next for Anderson is Van Barneveld, who came from 2 0 down to defeat Dave Chisnall 10 5, winning seven straight legs to take charge of the game in mid match.
Raymond van Barneveld also booked his place in the last eight (Picture: Lawrence Lustig/PDC)
"Dave let me in with some missed doubles but I played really well in the middle of the match," said Van Barneveld.
Reigning champion and world champion Michael van Gerwen began with victory over Simon Whitlock and he was joined in the last eight by Robert Thornton, Adrian Lewis and Mensur Suljovic from the evening session's final first round matches.
The tournament concludes with Sunday's replica hermes bags outlet quarter final, semi final and final.
Unibet Masters Quarter Final Draw Sunday Phil Taylor v Peter Wright Gary Anderson v Raymond van Barneveld Robert Thornton v Adrian Lewis Michael van Gerwen v Mensur Suljovic
Phil Taylor's last year on the PDC circuit began with victory over Michael Smith at the Unibet Masters, while Gary Anderson set up a clash with Raymond van Barneveld.
On Friday, Taylor reaffirmed what he had hinted at after his World Championship defeat to 'Barney' in December, that 2017 would be his last year on the circuit, with the 2018 World Championship being his last event.
The Power had admitted during the Worlds that he intended to just play the TV tournaments and the events that his ranking got him into during 2017, but confirmation of his impending retirement means the year will now become something of a farewell tour for the 16 time world champion
With the news out in the open, Taylor romped past Michael Smith, winning eight of the final 10 legs in Milton Keynes to seal a victory that sets up a quarter final date with third seed Peter Wright, who beat Ian White 10 5.
Unibet Masters First Round Friday's Results Dave Chisnall 5 10 Raymond van Barneveld Peter Taylor 10 6 Michael Smith Gary Anderson 10 3 Benito how much is a hermes handbag van de Pas Peter Wright 10 5 Ian White Saturday's Matches Mensur Suljovic 10 4 Jelle Klaasen James Wade 9 10 Robert Thornton Michael van Gerwen 10 6 Simon Whitlock Adrian Lewis 10 6 Kim Huybrechts
Taylor was delighted with his display and is looking forward to enjoying his final year on the circuit:
"I think I'm more excited now and I've got butterflies, whereas I didn't have that before. Perhaps that will do me good," he said.
Peter Wright will be up next for Taylor (Picture: Lawrence Lustig/PDC)
"This is a brilliant start. copy hermes bags I've got new darts and they were going lovely. I missed a few doubles and I went 4 2 down and clambered back to five each, and then I had a chance and double seven was lovely tonight."
World number two Gary Anderson produced the most impressive performance of the opening night, averaging almost 110 in a 10 3 demolition of Masters debutant Benito van de Pas.
Van de Pas weathered an early barrage from Anderson to land an 11 darter as he stayed in touch at 3 2, but the two time world champion reeled off the next five legs without reply before bettering the Dutchman's 128 fake hermes leather handbags checkout with a 142 finish to wrap up the win.
"I've had two weeks off since the World Championship without throwing a dart and it's worked," said Anderson.
"I've had a break and it's been great. I've enjoyed the couple of weeks back at home but I've got my head back on now and we'll see what happens."
Up next for Anderson is Van Barneveld, who came from 2 0 down to defeat Dave Chisnall 10 5, winning seven straight legs to take charge of the game in mid match.
Raymond van Barneveld also booked his place in the last eight (Picture: Lawrence Lustig/PDC)
"Dave let me in with some missed doubles but I played really well in the middle of the match," said Van Barneveld.
Reigning champion and world champion Michael van Gerwen began with victory over Simon Whitlock and he was joined in the last eight by Robert Thornton, Adrian Lewis and Mensur Suljovic from the evening session's final first round matches.
The tournament concludes with Sunday's replica hermes bags outlet quarter final, semi final and final.
Unibet Masters Quarter Final Draw Sunday Phil Taylor v Peter Wright Gary Anderson v Raymond van Barneveld Robert Thornton v Adrian Lewis Michael van Gerwen v Mensur Suljovic
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Pioglitazone use and risk of bladder cancer
AbstractObjectiveTo determine whether pioglitazone compared with other antidiabetic drugs is associated with an increased risk of bladder cancer in people with type 2 diabetes.ParticipantsA cohort of 145806 patients newly treated with antidiabetic drugs between 1 January 2000 and 31 July 2013, with follow up until 31 July 2014.Main outcome measuresThe use of pioglitazone was treated as a time varying variable, with use lagged by one year for latency purposes. Cox proportional hazards models were used to estimate adjusted hazard ratios with 95% confidence intervals of incident bladder cancer associated with pioglitazone overall and by both cumulative duration of use and cumulative dose. Similar analyses were conducted for rosiglitazone, a thiazolidinedione not previously associated with an increased risk of bladder cancer.ResultsThe cohort generated 689616 person years of follow up, during which 622 patients were newly diagnosed as having bladder cancer (crude incidence 90.2 per 100000 person years). Compared with other antidiabetic drugs, pioglitazone was associated with an increased risk of bladder cancer (121.0 v 88.9 per 100000 person years; hazard ratio 1.63, 95% confidence interval 1.22 to 2.19). Conversely, rosiglitazone was not associated with an increased risk of bladder cancer (86.2 v 88.9 per 100000 person years; 1.10, 0.83 to 1.47). Duration response and dose response relations brown hermes belt replica were observed for pioglitazone but not for rosiglitazone.ConclusionThe results of this large population based study indicate that pioglitazone is associated with an increased risk of bladder cancer. The absence of an association with rosiglitazone suggests that the increased risk is drug specific and not a class effect.IntroductionPioglitazone, an antidiabetic drug belonging to the thiazolidinedione class, has been shown to improve glycaemic levels in people with type 2 diabetes.1 However, in 2005 the PROactive randomised controlled trial unexpectedly showed an imbalance in the number of cases of bladder cancer with pioglitazone compared with placebo.2 In contrast, this imbalance was never observed in randomised controlled trials of rosiglitazone, the other approved drug belonging to the thiazolidinedione class.1 3The findings of the PROactive trial were subsequently corroborated in some,4 5 6 7 8 9 10 but not all, observational studies.11 12 13 14 15 16 17 18 19 Indeed, in the five year interim analysis of a large observational study using the Kaiser Permanente Northern California database,4 the use of pioglitazone for 24 months or more was associated with an increased risk of bladder cancer (hazard ratio 1.4, 95% confidence interval 1.03 to 2.0). However, in the final analysis of the Kaiser Permanente Northern California study, which used the same cohort4 with follow up extended to 10 years, the use of pioglitazone was no longer significantly associated with an increased risk of bladder cancer in a duration response fashion.20 These null findings are also consistent with those of another large multicohort study.19 The apparent heterogeneity in this literature may be due to methodological limitations, such as the inclusion of prevalent users,5 6 10 11 12 13 14 18 time lag bias,15 immortal time bias,10 14 18 and no consideration of disease latency.8 10 12 17 18Given these discrepant findings, the methodological shortcoming of previous studies examining this association, and the apparent loss of an association in studies with longer follow up,20 additional studies are needed to investigate further the association between pioglitazone and bladder cancer. In a large, population based study we assessed the association between the use of pioglitazone and bladder cancer in people with type Hermes belt replica paris 2 diabetes.MethodsData sourceThis study was conducted using the United Kingdom Clinical Practice Research Datalink (CPRD). The CPRD collects information on anthropometric variables such as body mass index and lifestyle variables such as smoking. Data collected in the CPRD have been previously validated and shown to be of high quality.22 23 Furthermore, cancer diagnoses have been found to be highly consistent with those recorded in the UK national cancer data repository.24Study populationBase cohortWe assembled a base cohort composed of all people newly treated for type 2 diabetes, defined as receiving a first ever prescription for a non insulin antidiabetic drug (metformin, sulfonylureas, prandial glucose regulators, thiazolidinediones, acarbose, dipeptidyl peptidase 4 (DPP 4) inhibitors, glucagon like peptide (GLP 1) agonists, sodium glucose cotransporter 2 (SGLT2) inhibitors) between 1 January 1988 and 31 July 2013. Patients were required to be at least 40 years of age and to have at least one year of CPRD medical history before that first prescription. We excluded patients prescribed insulin any time before their first non insulin antidiabetic prescription (as these may represent those with an advanced form of type 2 diabetes), and patients with a diagnosis of gestational diabetes and polycystic ovary syndrome (as these are other indications for metformin).Study cohortUsing the base cohort, we identified all patients who hermes belt price replica initiated a new antidiabetic drug class on or after 1 January 2000 (the year pioglitazone and rosiglitazone entered the UK market) until 31 July 2013. These patients included those newly treated with an antidiabetic drug class, as well as those who switched to or added on an antidiabetic drug class not previously used in their treatment. Cohort entry was defined by the date of this new prescription. We excluded all patients with a diagnosis of bladder cancer (including malignant, in situ, and benign lesions) at any time before cohort entry, as well as those with less than one year of follow up after cohort entry. The latter was necessary for latency considerations, as short term drug use are unlikely to cause incident bladder cancer.All patients were followed from the year after cohort entry until a first ever diagnosis of bladder cancer (malignant and in situ), or censored on death from any cause, end of registration with the general practice, or end of the study period (31 July 2014), whichever occurred first.Use of thiazolidinedionesIn the models we entered the use of thiazolidinediones as a time varying variable and classified it according to one of the four mutually exclusive categories: pioglitazone use, rosiglitazone use, pioglitazone and rosiglitazone use (mainly switchers), and no thiazolidinedione use. Patients were considered unexposed to thiazolidinediones until the time of the first thiazolidinedione prescription and thereafter considered exposed, after accounting for a one year lag period. This lag period was necessary to take into account a latency time window and to minimise possible detection bias around the time of treatment initiation. This was considered the primary exposure definition.In secondary analyses, we determined whether there was a duration response and dose response relation between pioglitazone and incidence of bladder cancer. The duration response relation was assessed in terms of cumulative duration of use, which was defined, in a time dependent fashion, as the total number of years of use, calculated by summing the durations of all prescriptions received between cohort entry and the time of the event. This variable was then classified using the same categories used in the interim analysis of the Kaiser Permanente Northern California study4: 2 years of use. We also assessed cumulative duration on a continuous scale using a restricted cubic spline model with five knots.25 Dose response was assessed in terms of cumulative dose, which was calculated in a time dependent fashion as the sum of all doses received up until the date of the event. This variable was also categorised using the same cut offs used in previous studies4 5: 10500 mg, 10501 28000 mg, and >28000 mg. We assessed the linear trend for cumulative duration of use and dose by considering these variables as continuous in the models.For comparison purposes we also assessed whether there was a duration response and dose response relation with rosiglitazone, in terms of cumulative duration of use (categorically (2 years) and continuously using restricted cubic spline modelling) and cumulative dose (categorised on the basis of the distribution of use in thirds in the cohort). We also conducted two secondary analyses to assess whether there were duration response and dose response relations with pioglitazone and risk of bladder cancer in terms of cumulative duration of use and cumulative dose (as defined previously). Identical analyses were done for rosiglitazone. For all models we used the model proposed by Fine and Gray to account for competing risks due to death from any cause.27 We examined the Schoenfeld residuals for the time fixed covariates and found no important departures from the proportional hazards assumption.Sensitivity analysesWe conducted nine sensitivity analyses to assess the robustness of our findings. Firstly, given uncertainties related to the latency time window, we repeated the primary analysis with lag periods of zero and two years. Secondly, we repeated the primary analysis after considering a stricter definition for drug use based on receiving at least four prescriptions within a 12 month window. Thirdly, we repeated the analysis after excluding patients with a history of bladder conditions at any time before cohort entry and censoring on a new diagnosis during follow up. Fourthly, we repeated the primary analysis after additionally censoring on a new diagnosis of benign bladder lesions, in situ bladder cancer, liver failure, and heart failure (the last two were also additional exclusion criteria). Indeed, thiazolidinediones are contraindicated or not recommended for the two last conditions, the presence of which may lead to thiazolidinedione discontinuation or may influence treatment decisions. Fifthly, in 2011 several regulatory actions were issued because of the potential association between pioglitazone and bladder cancer.28 We performed a sensitivity analysis censoring follow up to 31 December 2010, as it is possible that patients starting or continuing pioglitazone after that date may have been more carefully screened for bladder cancer. Sixthly, we repeated the primary analysis using multiple imputation for variables with missing values (that is, body mass index, smoking, and haemoglobin A1c).29 30 Seventhly, we additionally adjusted the models for the time dependent use of other antidiabetic drugs (metformin, sulfonylureas, incretin based drugs (GLP 1 analogues or DPP 4 inhibitors), insulin, and other oral hypoglycaemic drugs) during follow up, lagged by one year for latency considerations. Eighthly, to account for potential time dependent confounding during the 14.5 year study period, we repeated the primary analysis using a marginal structural Cox proportional hazards model with inverse probability of treatment and censoring weighting (see the supplementary file for a detailed description of this method). Finally, we assessed the strength of an unmeasured confounder needed to move the estimated hazard ratio to the null using the "rule out" method proposed by Schneeweiss.31Head to head comparison of pioglitazone with rosiglitazoneTo assess further whether an association between pioglitazone and bladder cancer is a drug specific compared with a class effect, we conducted two additional analyses that directly compared pioglitazone with rosiglitazone. In the first approach, we contrasted the use of pioglitazone with the use of rosiglitazone by repeating our primary analysis with the latter as the reference category. In the second approach, we used the study cohort to assemble a subcohort of patients starting pioglitazone or rosiglitazone between 1 January 2000 and 31 July 2013, with follow up until 31 July 2014. As with the primary analysis, all patients were required to have at least one year of follow up after their first prescription for a thiazolidinedione. Consequently, cohort entry was set as the year after the first thiazolidinedione prescription during the study period. All patients were followed until a first ever diagnosis of bladder cancer, or censored on death from any cause, switching to another thiazolidinedione, end of registration with the general practice, or end of the study period, Hermes belts replica paris whichever occurred first. The model was adjusted for high dimensional propensity scores,32 which included the prespecified variables listed previously along with another 500 empirically defined variables measured at the time of the first thiazolidinedione prescription. All analyses were conducted with SAS version 9.4 (SAS Institute, Cary, NC).Patient involvementNo patients were involved in setting the research question or the outcome measure, nor were they involved in developing plans for design or implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research to study participants or the relevant patient community.ResultsA total of 145806 patients met the study inclusion criteria (see supplementary figure 1). Overall, the cohort was followed for a mean of 4.7 (SD 3.4) years, generating 689616 person years of follow up. Overall, 622 patients received a diagnosis of bladder cancer during follow up, yielding a crude incidence rate of 90.2 (95% confidence interval 83.2 to 97.6) per 100000 person years. Among patients with an event, the median time between cohort entry and an incident diagnosis of bladder cancer was 4.4 (interquartile range 2.5 6.5) years.Table 1 presents the characteristics of the cohort overall and stratified by pioglitazone users versus non thiazolidinedione users at baseline. Compared with non thiazolidinedione users, pioglitazone users were less likely to be obese but more likely to have increased haemoglobin A1c levels, to have undergone urine protein testing before cohort entry, had a longer duration of treated diabetes, and were more likely to have previous bladder conditions. Pioglitazone users were also more likely to have used sulfonylureas and less likely to have received metformin compared with non users of thiazolidinediones. The baseline characteristics of rosiglitazone users are similar and shown in supplementary table 1.Table 1 Baseline characteristics of cohort overall and stratified by users and non users of pioglitazone at cohort entry. Values are numbers (percentages) unless stated otherwiseView this table:View popupView inlineOverall, the use of rosiglitazone was not associated with an increased risk of incident bladder cancer (86.2 v 88.9 per 100000 person years, adjusted hazard ratio 1.10, 95% confidence interval 0.83 to 1.47; see supplementary table 2). Similarly, there was no evidence of a duration response relation in terms of cumulative duration of use when it was classified as a categorical variable (P=0.7 for trend; see supplementary table 2) or when it was considered as a continuous variable (see supplementary figure 2). Finally, there was no evidence of a dose response relation in terms of cumulative dose (P=0.7 for trend; see supplementary table 2).
AbstractObjectiveTo determine whether pioglitazone compared with other antidiabetic drugs is associated with an increased risk of bladder cancer in people with type 2 diabetes.ParticipantsA cohort of 145806 patients newly treated with antidiabetic drugs between 1 January 2000 and 31 July 2013, with follow up until 31 July 2014.Main outcome measuresThe use of pioglitazone was treated as a time varying variable, with use lagged by one year for latency purposes. Cox proportional hazards models were used to estimate adjusted hazard ratios with 95% confidence intervals of incident bladder cancer associated with pioglitazone overall and by both cumulative duration of use and cumulative dose. Similar analyses were conducted for rosiglitazone, a thiazolidinedione not previously associated with an increased risk of bladder cancer.ResultsThe cohort generated 689616 person years of follow up, during which 622 patients were newly diagnosed as having bladder cancer (crude incidence 90.2 per 100000 person years). Compared with other antidiabetic drugs, pioglitazone was associated with an increased risk of bladder cancer (121.0 v 88.9 per 100000 person years; hazard ratio 1.63, 95% confidence interval 1.22 to 2.19). Conversely, rosiglitazone was not associated with an increased risk of bladder cancer (86.2 v 88.9 per 100000 person years; 1.10, 0.83 to 1.47). Duration response and dose response relations brown hermes belt replica were observed for pioglitazone but not for rosiglitazone.ConclusionThe results of this large population based study indicate that pioglitazone is associated with an increased risk of bladder cancer. The absence of an association with rosiglitazone suggests that the increased risk is drug specific and not a class effect.IntroductionPioglitazone, an antidiabetic drug belonging to the thiazolidinedione class, has been shown to improve glycaemic levels in people with type 2 diabetes.1 However, in 2005 the PROactive randomised controlled trial unexpectedly showed an imbalance in the number of cases of bladder cancer with pioglitazone compared with placebo.2 In contrast, this imbalance was never observed in randomised controlled trials of rosiglitazone, the other approved drug belonging to the thiazolidinedione class.1 3The findings of the PROactive trial were subsequently corroborated in some,4 5 6 7 8 9 10 but not all, observational studies.11 12 13 14 15 16 17 18 19 Indeed, in the five year interim analysis of a large observational study using the Kaiser Permanente Northern California database,4 the use of pioglitazone for 24 months or more was associated with an increased risk of bladder cancer (hazard ratio 1.4, 95% confidence interval 1.03 to 2.0). However, in the final analysis of the Kaiser Permanente Northern California study, which used the same cohort4 with follow up extended to 10 years, the use of pioglitazone was no longer significantly associated with an increased risk of bladder cancer in a duration response fashion.20 These null findings are also consistent with those of another large multicohort study.19 The apparent heterogeneity in this literature may be due to methodological limitations, such as the inclusion of prevalent users,5 6 10 11 12 13 14 18 time lag bias,15 immortal time bias,10 14 18 and no consideration of disease latency.8 10 12 17 18Given these discrepant findings, the methodological shortcoming of previous studies examining this association, and the apparent loss of an association in studies with longer follow up,20 additional studies are needed to investigate further the association between pioglitazone and bladder cancer. In a large, population based study we assessed the association between the use of pioglitazone and bladder cancer in people with type Hermes belt replica paris 2 diabetes.MethodsData sourceThis study was conducted using the United Kingdom Clinical Practice Research Datalink (CPRD). The CPRD collects information on anthropometric variables such as body mass index and lifestyle variables such as smoking. Data collected in the CPRD have been previously validated and shown to be of high quality.22 23 Furthermore, cancer diagnoses have been found to be highly consistent with those recorded in the UK national cancer data repository.24Study populationBase cohortWe assembled a base cohort composed of all people newly treated for type 2 diabetes, defined as receiving a first ever prescription for a non insulin antidiabetic drug (metformin, sulfonylureas, prandial glucose regulators, thiazolidinediones, acarbose, dipeptidyl peptidase 4 (DPP 4) inhibitors, glucagon like peptide (GLP 1) agonists, sodium glucose cotransporter 2 (SGLT2) inhibitors) between 1 January 1988 and 31 July 2013. Patients were required to be at least 40 years of age and to have at least one year of CPRD medical history before that first prescription. We excluded patients prescribed insulin any time before their first non insulin antidiabetic prescription (as these may represent those with an advanced form of type 2 diabetes), and patients with a diagnosis of gestational diabetes and polycystic ovary syndrome (as these are other indications for metformin).Study cohortUsing the base cohort, we identified all patients who hermes belt price replica initiated a new antidiabetic drug class on or after 1 January 2000 (the year pioglitazone and rosiglitazone entered the UK market) until 31 July 2013. These patients included those newly treated with an antidiabetic drug class, as well as those who switched to or added on an antidiabetic drug class not previously used in their treatment. Cohort entry was defined by the date of this new prescription. We excluded all patients with a diagnosis of bladder cancer (including malignant, in situ, and benign lesions) at any time before cohort entry, as well as those with less than one year of follow up after cohort entry. The latter was necessary for latency considerations, as short term drug use are unlikely to cause incident bladder cancer.All patients were followed from the year after cohort entry until a first ever diagnosis of bladder cancer (malignant and in situ), or censored on death from any cause, end of registration with the general practice, or end of the study period (31 July 2014), whichever occurred first.Use of thiazolidinedionesIn the models we entered the use of thiazolidinediones as a time varying variable and classified it according to one of the four mutually exclusive categories: pioglitazone use, rosiglitazone use, pioglitazone and rosiglitazone use (mainly switchers), and no thiazolidinedione use. Patients were considered unexposed to thiazolidinediones until the time of the first thiazolidinedione prescription and thereafter considered exposed, after accounting for a one year lag period. This lag period was necessary to take into account a latency time window and to minimise possible detection bias around the time of treatment initiation. This was considered the primary exposure definition.In secondary analyses, we determined whether there was a duration response and dose response relation between pioglitazone and incidence of bladder cancer. The duration response relation was assessed in terms of cumulative duration of use, which was defined, in a time dependent fashion, as the total number of years of use, calculated by summing the durations of all prescriptions received between cohort entry and the time of the event. This variable was then classified using the same categories used in the interim analysis of the Kaiser Permanente Northern California study4: 2 years of use. We also assessed cumulative duration on a continuous scale using a restricted cubic spline model with five knots.25 Dose response was assessed in terms of cumulative dose, which was calculated in a time dependent fashion as the sum of all doses received up until the date of the event. This variable was also categorised using the same cut offs used in previous studies4 5: 10500 mg, 10501 28000 mg, and >28000 mg. We assessed the linear trend for cumulative duration of use and dose by considering these variables as continuous in the models.For comparison purposes we also assessed whether there was a duration response and dose response relation with rosiglitazone, in terms of cumulative duration of use (categorically (2 years) and continuously using restricted cubic spline modelling) and cumulative dose (categorised on the basis of the distribution of use in thirds in the cohort). We also conducted two secondary analyses to assess whether there were duration response and dose response relations with pioglitazone and risk of bladder cancer in terms of cumulative duration of use and cumulative dose (as defined previously). Identical analyses were done for rosiglitazone. For all models we used the model proposed by Fine and Gray to account for competing risks due to death from any cause.27 We examined the Schoenfeld residuals for the time fixed covariates and found no important departures from the proportional hazards assumption.Sensitivity analysesWe conducted nine sensitivity analyses to assess the robustness of our findings. Firstly, given uncertainties related to the latency time window, we repeated the primary analysis with lag periods of zero and two years. Secondly, we repeated the primary analysis after considering a stricter definition for drug use based on receiving at least four prescriptions within a 12 month window. Thirdly, we repeated the analysis after excluding patients with a history of bladder conditions at any time before cohort entry and censoring on a new diagnosis during follow up. Fourthly, we repeated the primary analysis after additionally censoring on a new diagnosis of benign bladder lesions, in situ bladder cancer, liver failure, and heart failure (the last two were also additional exclusion criteria). Indeed, thiazolidinediones are contraindicated or not recommended for the two last conditions, the presence of which may lead to thiazolidinedione discontinuation or may influence treatment decisions. Fifthly, in 2011 several regulatory actions were issued because of the potential association between pioglitazone and bladder cancer.28 We performed a sensitivity analysis censoring follow up to 31 December 2010, as it is possible that patients starting or continuing pioglitazone after that date may have been more carefully screened for bladder cancer. Sixthly, we repeated the primary analysis using multiple imputation for variables with missing values (that is, body mass index, smoking, and haemoglobin A1c).29 30 Seventhly, we additionally adjusted the models for the time dependent use of other antidiabetic drugs (metformin, sulfonylureas, incretin based drugs (GLP 1 analogues or DPP 4 inhibitors), insulin, and other oral hypoglycaemic drugs) during follow up, lagged by one year for latency considerations. Eighthly, to account for potential time dependent confounding during the 14.5 year study period, we repeated the primary analysis using a marginal structural Cox proportional hazards model with inverse probability of treatment and censoring weighting (see the supplementary file for a detailed description of this method). Finally, we assessed the strength of an unmeasured confounder needed to move the estimated hazard ratio to the null using the "rule out" method proposed by Schneeweiss.31Head to head comparison of pioglitazone with rosiglitazoneTo assess further whether an association between pioglitazone and bladder cancer is a drug specific compared with a class effect, we conducted two additional analyses that directly compared pioglitazone with rosiglitazone. In the first approach, we contrasted the use of pioglitazone with the use of rosiglitazone by repeating our primary analysis with the latter as the reference category. In the second approach, we used the study cohort to assemble a subcohort of patients starting pioglitazone or rosiglitazone between 1 January 2000 and 31 July 2013, with follow up until 31 July 2014. As with the primary analysis, all patients were required to have at least one year of follow up after their first prescription for a thiazolidinedione. Consequently, cohort entry was set as the year after the first thiazolidinedione prescription during the study period. All patients were followed until a first ever diagnosis of bladder cancer, or censored on death from any cause, switching to another thiazolidinedione, end of registration with the general practice, or end of the study period, Hermes belts replica paris whichever occurred first. The model was adjusted for high dimensional propensity scores,32 which included the prespecified variables listed previously along with another 500 empirically defined variables measured at the time of the first thiazolidinedione prescription. All analyses were conducted with SAS version 9.4 (SAS Institute, Cary, NC).Patient involvementNo patients were involved in setting the research question or the outcome measure, nor were they involved in developing plans for design or implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research to study participants or the relevant patient community.ResultsA total of 145806 patients met the study inclusion criteria (see supplementary figure 1). Overall, the cohort was followed for a mean of 4.7 (SD 3.4) years, generating 689616 person years of follow up. Overall, 622 patients received a diagnosis of bladder cancer during follow up, yielding a crude incidence rate of 90.2 (95% confidence interval 83.2 to 97.6) per 100000 person years. Among patients with an event, the median time between cohort entry and an incident diagnosis of bladder cancer was 4.4 (interquartile range 2.5 6.5) years.Table 1 presents the characteristics of the cohort overall and stratified by pioglitazone users versus non thiazolidinedione users at baseline. Compared with non thiazolidinedione users, pioglitazone users were less likely to be obese but more likely to have increased haemoglobin A1c levels, to have undergone urine protein testing before cohort entry, had a longer duration of treated diabetes, and were more likely to have previous bladder conditions. Pioglitazone users were also more likely to have used sulfonylureas and less likely to have received metformin compared with non users of thiazolidinediones. The baseline characteristics of rosiglitazone users are similar and shown in supplementary table 1.Table 1 Baseline characteristics of cohort overall and stratified by users and non users of pioglitazone at cohort entry. Values are numbers (percentages) unless stated otherwiseView this table:View popupView inlineOverall, the use of rosiglitazone was not associated with an increased risk of incident bladder cancer (86.2 v 88.9 per 100000 person years, adjusted hazard ratio 1.10, 95% confidence interval 0.83 to 1.47; see supplementary table 2). Similarly, there was no evidence of a duration response relation in terms of cumulative duration of use when it was classified as a categorical variable (P=0.7 for trend; see supplementary table 2) or when it was considered as a continuous variable (see supplementary figure 2). Finally, there was no evidence of a dose response relation in terms of cumulative dose (P=0.7 for trend; see supplementary table 2).